Method for treatment of parkinson&#39;s disease

ABSTRACT

Disclosed is a method for the treatment of a neurological or movement disorder, e.g., Parkinson&#39;s disease, in an individual in need thereof, by parenteral administration of levodopa and a dopa decarboxylase inhibitor (DDCI), such as carbidopa, benserazide or any combination thereof, concomitantly with oral administration of levodopa, a DDCI, such as carbidopa, benserazide, or any combination thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 17/334,554, filed May 28, 2021, which claims the benefit of andpriority to U.S. Provisional Patent Application No. 63/114,688, filedNov. 17, 2020, the disclosure of each of which is incorporated byreference herein in its entirety.

TECHNICAL FIELD

The present invention provides a method for treatment of neurological ormovement disorders such as Parkinson's disease by parenteraladministration of levodopa or prodrug thereof and a dopa decarboxylaseinhibitor (DDCI) or prodrug thereof, such as carbidopa, benserazide, orany combination thereof, concomitantly with oral administration oflevodopa or prodrug thereof, a dopa decarboxylase inhibitor (DDCI) orprodrug thereof, such as carbidopa, benserazide, or any combinationthereof.

BACKGROUND

Parkinson's disease is a degenerative condition characterized by reducedconcentration of the neurotransmitter dopamine in the brain. Levodopa(L-dopa or L-3,4-dihydroxyphenylalanine) is an immediate metabolicprecursor of dopamine that, unlike dopamine, is able to cross theblood-brain barrier, and is most commonly used for restoring thedopamine concentration in the brain. For the past 40 years, levodopa hasremained the most effective therapy for the treatment of Parkinson'sdisease.

However, levodopa has a short half-life in plasma that, even under bestcommon current standard of care, results in pulsatile dopaminergicstimulation. Long-term therapy is therefore complicated by motorfluctuations and dyskinesia that can represent a source of significantdisability for certain patients. A therapeutic strategy that couldultimately deliver levodopa/dopamine to the brain in a more continuousand physiologic manner would provide the benefits of standard levodopawith reduced motor complications and is much needed by patientssuffering from Parkinson's disease and other neurological or movementdisorders.

SUMMARY OF INVENTION

Provided herein, inter alia, are methods and pharmaceutical compositionsfor the treatment of a neurological or movement disorder comprisingparenteral administration of levodopa, prodrugs or salts thereof (e.g.,pharmaceutically acceptable prodrugs or salts thereof), and compositionscomprising the same (e.g., pharmaceutically acceptable compositions, forexample, liquid pharmaceutical compositions) and a dopa decarboxylaseinhibitor (DDCI), prodrugs or salts thereof (e.g., pharmaceuticallyacceptable prodrugs or salts thereof), and compositions comprising thesame (e.g., pharmaceutically acceptable compositions, for example,liquid pharmaceutical compositions) concomitant with oral administrationof an active agent selected from the group consisting of levodopa, alevodopa salt, a levodopa prodrug, a dopa decarboxylase inhibitor(DDCI), prodrugs or salts thereof (e.g., pharmaceutically acceptablesalts thereof), and compositions comprising the same (e.g.,pharmaceutically acceptable compositions, for example, liquidpharmaceutical compositions). Also disclosed is a kit for theadministration of the described method and treatment regimens foradministration of the described method specified by time course andamount of pharmaceutical composition.

Embodiments of the invention are directed to a method for treatment ofParkinson's disease in a patient in need thereof, said methodcomprising:

subcutaneously administering to the patient, over a subcutaneousinfusion time course of at least about 24 hours, a pharmaceuticallyacceptable liquid composition comprising levodopa and carbidopa in anamount to deliver about 720 mg of levodopa and about 90 mg of carbidopato the patient over the time course of the at least about 24 hours; and

orally administering to the patient, before or during the subcutaneousinfusion time course, one or more immediate release tablet or capsulecomprising 100 mg levodopa.

According to some embodiments, the pharmaceutically acceptable liquidcomposition further comprises arginine. According to some embodiments,the pharmaceutically acceptable liquid composition further comprises atleast one antioxidant. According to some embodiments, the immediaterelease tablet or capsule further comprises carbidopa.

According to some embodiments, upon the subcutaneous administration andthe oral administration, the plasma levodopa area under the curve (AUC)from time 0 to the end of the infusion time of the patient is higher ascompared to the combination of i) a plasma levodopa AUC from time 0 tothe end of the infusion time when a patient is subcutaneouslyadministered over at least about 24 hours the pharmaceuticallyacceptable liquid composition alone; and ii) a plasma levodopa AUC of apatient administered with the oral levodopa alone.

Further embodiments of the invention are directed to a method fortreatment of Parkinson's disease in a patient in need thereof, saidmethod comprising:

subcutaneously administering to the patient, over a subcutaneousinfusion time course of at least about 24 hours or more, a firstpharmaceutically acceptable liquid composition comprising: levodopa,carbidopa, arginine, and an antioxidant, in an amount to deliver about720 mg of levodopa and about 90 mg of carbidopa to the patient over thecourse of at least about 24 hours; and

orally administering to the patient, before or during the subcutaneousinfusion time course, at least one oral dosage form comprising levodopa.

According to some embodiments, the oral dosage form includes one of: 50mg levodopa, 75 mg levodopa, 95 mg levodopa, 100 mg levodopa, 125 mglevodopa, 145 mg levodopa, 150 mg levodopa, 195 mg levodopa, 200 mglevodopa, 245 mg levodopa, or 250 mg levodopa.

Further embodiments of the invention are directed to a method fortreatment of Parkinson's disease in a patient currently beingadministered levodopa and carbidopa in the form of oral immediaterelease levodopa and carbidopa alone, and in need of further treatment,said method comprising:

subcutaneously administering to the patient, over a subcutaneousinfusion time course of 24 hours a first pharmaceutically acceptableliquid composition comprising: levodopa, carbidopa, arginine, and anantioxidant, in an amount to deliver about 720 mg of levodopa and about90 mg of carbidopa to the patient over the course of at least about 24hours;

orally administering to the patient, before or during the subcutaneousinfusion time course, at least one tablet or capsule comprising 100 mglevodopa and 25 mg carbidopa daily.

Disclosed herein is a method for treatment of a neurological or movementdisorder in a patient in need thereof, said method comprising:parenterally administering to the patient a first pharmaceuticalcomposition comprising: a) levodopa, a levodopa salt, a levodopaprodrug, or any combination thereof; and b) a dopa decarboxylaseinhibitor (DDCI), a DDCI salt, a DDCI prodrug, or any combinationthereof; and, concomitantly, orally administering to the patient asecond pharmaceutical composition comprising an active agent selectedfrom the group consisting of levodopa, a levodopa salt, a levodopaprodrug, a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCIprodrug, and any combination thereof.

In some embodiments, the method described herein includes a DDCIcomprising, consisting of, or consisting essentially of carbidopa,benserazide, or any combination thereof.

In some embodiments, the method described herein includes the same DDCIin the first pharmaceutical composition as the DDCI in the secondpharmaceutical composition.

In some embodiments, the method described herein includes a differentDDCI in the first pharmaceutical composition as the DDCI in the secondpharmaceutical composition

In some embodiments, the method described herein includes as the secondpharmaceutical composition levodopa and a DDCI.

In some embodiments, the method described herein includes the DDCIcarbidopa.

In some embodiments, the method described herein includes subcutaneous,transdermal, intradermal, intravenous, intramuscular, intratracheal,intranasal, intrathecal, intragastric or intraduodenal administration ofthe first pharmaceutical composition.

In some embodiments, the method described herein includes subcutaneousadministration of the first pharmaceutical composition.

In some embodiments, the method described herein includes theadministration of the pharmaceutical composition to the patient in needthereof via one or more sites.

In some embodiments, the neurological or movement disorder pertaining tothe method described herein includes Parkinson's disease; secondaryparkinsonism, such as drug-induced secondary parkinsonism, neurolepticinduced parkinsonism, postencephalitic parkinsonism, and vascularparkinsonism; motor fluctuations; neurodegenerative disorders;dyskinesia; reduced dopamine levels in the brain; levodopa induceddyskinesia; rapid eye movement sleep behavior disorder (RBD); dystonia;morning akinesia; tremor symptoms, such as essential tremor anddrug-induced tremor; myoclonus; chorea, such as drug induced chorea;tics, such as drug induced tics and organic tics; drug induced movementdisorder; drug induced akathisia; restless legs syndrome (RLS);stiff-man syndrome; benign shuddering attacks; malignant neurolepticsyndrome; Huntington's disease; Shy-Drager syndrome; brain injuryinduced conditions, such as carbon monoxide or manganese intoxication;or any combination thereof; for example, provided herein are methods oftreating patients suffering from includes Parkinson's disease.

Generally, physicians assess the severity of Parkinson's diseasepatients according to objective and subjective signs and symptoms,using, e.g., various scales, and prescribe levodopa dosingadministration accordingly. One of the well-known and widely used scalesfor diagnosing and scaling the severity of Parkinson's disease is theUnified Parkinson's Disease Rating Scale (UPDRS). Modifications of theUPDRS may also be used to classify Parkinson's disease patients. Anotherknown method for measuring the severity of Parkinson's disease isaccording to the Hoehn and Yahr (H&Y) stages, which includes a scale of5 stages, in which stages 1-2 are considered to be mild or early-stageParkinson's disease patients, stage 3 is considered to be moderate ormid-stage Parkinson's disease patients, and stages 4-5 are considered tobe advanced Parkinson's disease patients. The daily levodopa dose may bedefined and changed by the physician from time to time, according to,e.g., clinical findings as well as “trial and error” methods, accordingto the particular patient's condition, the response of that patient tothe treatment, and the like. Further, the patient may be administered adifferent daily dose on different days, depending on signs and symptoms,wherein the range of the administered daily dose may be set by thephysician, thereby allowing the patient flexibility in treatment. It isnoted that physician generally refer to signs as being objective measureand to symptoms as being subjective ones.

According to some embodiments, provided herein are methods of treatingadvance-stage Parkinson's disease patients. According to someembodiments, provided herein are methods of treating advanced stageand/or moderate Parkinson's disease patients. According to someembodiments, provided herein are methods for treating patients withmotor fluctuations. According to some embodiments, provided herein aremethods for treating Parkinson's disease patients with motorfluctuations.

According to some embodiments, provided herein are methods of treatingParkinson's disease patients who require a dose of above about 300 mglevodopa/day, above about 400 mg levodopa/day, above about 500 mglevodopa/day, above about 600 mg levodopa/day, above about 700 mglevodopa/day, above about 800 mg levodopa/day, above about 900 mglevodopa/day, above about 1000 mg levodopa/day.

According to some embodiments, provided herein are methods of treatingParkinson's disease patients requiring an elevated dose of levodopa at aparticular timepoint, e.g., in the morning, e.g., towards the end (aboutthe last hour) of a low activity/night period, e.g., in the beginning(about the first hour) of a high activity/day period. For instance,according to some embodiments, there may be a certain rate for highactivity/day hours and a different rate for low activity/night hours,wherein an elevated dose of levodopa may be administered towards the endof the low activity/night hours, at the end of the low activity/nighthours, at the beginning of the high activity/day hours, and the like.Such an elevated dose may be provided by the administration of an oraldose of the second pharmaceutical composition, e.g., at the timesreferred to above, provided concomitantly with the substantiallycontinuous first pharmaceutical composition.

According to some embodiments, provided herein are methods of treatingpatients suffering from Parkinson's disease for a period of more thanabout 4 years, more than about 5 years, more than about 6 years, morethan about 7 years, more than about 8 years, more than about 9 years, ormore than about 10 years.

According to some embodiments, provided herein are methods of treatingParkinson's disease patients suffering from at least 1 hour, at least1.5 hours, at least 2 hours, at least 2.5 hours, at least 3 hours, of“off time” per day, wherein “off time” refers to the recurrence ofParkinson's symptoms between medication doses.

In some embodiments, the method described herein includes substantialcontinuous administration of the first pharmaceutical composition.

In some embodiments, the method described herein includes administrationof the second pharmaceutical composition 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10times a day.

In some embodiments, the method described herein includes administrationof the second pharmaceutical composition when symptoms from saidneurological or movement disorder require said administration.

In some embodiments, the method described herein includes administrationof the second pharmaceutical composition at predefined times, predefinedintervals, or both.

In some embodiments, the method described herein includes administrationof the second pharmaceutical composition more than once, wherein theadministered dose is the same at all administrations.

In some embodiments, the method described herein includes administrationof the second pharmaceutical composition more than once, wherein theadministered dose differs in at least two administrations.

In some embodiments, the method described herein includes administrationof the second pharmaceutical composition in a dose of between about 25mg and about 400 mg levodopa or a salt or prodrug thereof, in eachadministration.

In some embodiments, the method described herein includes as the firstpharmaceutical composition levodopa, carbidopa and arginine or any saltor prodrug thereof.

In some embodiments, the method described herein includes as the firstpharmaceutical composition levodopa, carbidopa, arginine, or any salt orprodrug thereof, and at least one antioxidant.

In some embodiments, the method described herein includes as the firstpharmaceutical composition levodopa, carbidopa, arginine, or any salt orprodrug thereof, and at least two antioxidants.

In some embodiments, the method described herein includes as the firstpharmaceutical composition a composition that comprises levodopa,carbidopa, or any salt or prodrug thereof, and a base selected from thegroup consisting of arginine, NaOH, tris(hydroxymethyl)aminomethane(TRIS), and any combination thereof.

In some embodiments, the method described herein includes as the firstpharmaceutical composition a composition with a pH in the range ofbetween about 6 to about 10, in the range of between about 8 to about10, in the range of between about 9 to about 10, in the range of betweenabout 9.1 to about 9.8, or about 9.5.

In some embodiments, the method described herein includes as the firstpharmaceutical composition a composition that comprises between about 1%w/v and about 40% w/v, between about 1% w/v and about 20% w/v, betweenabout 1% w/v and about 10% w/v, between about 2% w/v and about 8% w/v,between about 4% w/v and about 8% w/v, between about 5% w/v and about 7%w/v, or about 6% w/v of levodopa, a levodopa prodrug, a levodopa salt,or any combination thereof.

In some embodiments, the method described herein includes as the firstpharmaceutical composition a composition that comprises between about0.5% w/v and about 10% w/v, between about 0.5% w/v and about 6% w/v,between about 0.5% w/v and about 4% w/v, between about 0.5% w/v andabout 2% w/v, between about 0.5% w/v and about 1% w/v, about 0.75% w/vof carbidopa, a carbidopa salt, a carbidopa prodrug, or any combinationthereof.

In some embodiments, the method described herein includes theantioxidant that is selected from the group consisting of ascorbic acidor a salt thereof, a cysteine, such as N-acetyl cysteine, a bisulfite ora salt thereof, glutathione, a tyrosinase inhibitor, a bivalent cation,butylated hydroxy toluene (BHT), beta hydroxy acid (BHA) tocopherol,gentisic acid, tocopherol, tocopherol derivative, thioglycerol, and anycombination thereof.

In some embodiments, the method described herein includes as the firstpharmaceutical composition a composition that comprises between about0.05% w/v and about 2.0% w/v, between about 0.5% w/v and about 1.5% w/v,about 0.75% w/v, about 0.9% w/v, about 1.0% w/v, about 1.1% w/v, about1.25% w/v, of an antioxidant or a combination of antioxidants.

In some embodiments, the method described herein includes as the firstpharmaceutical composition a composition that comprises between about 5%w/v and about 30% w/v, between about 10% w/v and 20% w/v, between about12.5% w/v and 17.5% w/v, about 15% w/v, or about 15.2% w/v base.

In some embodiments, the method described herein includes administrationof the first pharmaceutical composition via one or two sites.

In some embodiments, the method described herein includes administrationof the first pharmaceutical composition at a volume of between about 1ml to about 30 ml per site per day, between about 2 ml to about 20 mlper site per day, between about 3 ml to about 10 ml per site per day,between about 5 ml to about 7 ml per site per day, or about 6 ml persite per day.

Also disclosed herein is a first pharmaceutical composition comprising:levodopa, a levodopa salt, a levodopa prodrug, or any combinationthereof; and a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCIprodrug, or any combination thereof; and, a second pharmaceuticalcomposition comprising: levodopa, a levodopa salt, a levodopa prodrug, adopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug; or anycombination thereof, for use as a combination in the treatment of aneurological or movement disorder, wherein the first pharmaceuticalcomposition is formulated as a parenteral composition and the secondpharmaceutical composition is formulated as an oral composition.

Also disclosed herein is a kit comprising: a first pharmaceuticalcomposition in parenteral form comprising: levodopa, a levodopa salt, alevodopa prodrug, or any combination thereof; and a dopa decarboxylaseinhibitor (DDCI), a DDCI salt, a DDCI prodrug, or any combinationthereof; a second pharmaceutical composition in oral form comprising:levodopa, a levodopa salt, a levodopa prodrug, a dopa decarboxylaseinhibitor (DDCI), a DDCI salt, a DDCI prodrug; or any combinationthereof; and instructions for the concomitant administration of thefirst pharmaceutical composition and the second pharmaceuticalcomposition for the treatment of a neurological or movement disorder.

Disclosed herein, in other embodiments, is a method for treatment of aneurological or movement disorder in a patient in need thereof, saidmethod comprising: subcutaneously administering to the patient, over asubcutaneous infusion time course of about 7 to about 10 hours or more(e.g., a time course of about 8 hours), a first pharmaceuticallyacceptable liquid composition comprising levodopa and carbidopa in anamount to deliver about 100 to 200 mg of levodopa and about 12 to about50 mg of carbidopa to the patient; and orally administering to thepatient, before or during the subcutaneous infusion time course, animmediate release tablet or capsule comprising levodopa and carbidopa.Contemplated immediate release tablets may include for example 50 mg, 75mg, 100 mg, 125 mg or 150 mg levodopa and/or may include 2.5 mg, 18.57mg, 25 mg, 31.25 mg, 37.5 mg or 50 mg carbidopa. In some embodiments,the method described herein includes an initial and/or concurrent oraladministration of the immediate release tablet or capsule with the startof the infusion time course, for example, oral administration of theimmediate release tablet or capsule may occur at substantially the sametime the infusion administration begins, and/or about 1, 2, 3, 4, or 5hours after the start of the infusion time course (e.g., at about 0hours or about 4 hours after the start of the infusion time course),and/or about 1, 2, 3, 4, or 5 hours before the start of the infusiontime course (e.g., at about 0 hours or about 4 hours before the start ofthe infusion time course).

In some embodiments, a method described herein includes the immediaterelease tablet or capsule that comprises 100 mg levodopa and 25 mgcarbidopa.

Methods described herein may include subcutaneous administration of thefirst pharmaceutically acceptable liquid composition that compriseslevodopa and carbidopa in an amount to deliver about 140 to 170 mg oflevodopa and about 16 to about 24 mg of carbidopa to the patient.Contemplated first pharmaceutically acceptable liquid composition mayinclude a liquid composition that comprises about 6% by weight levodopa,about 0.75% by weight carbidopa, and about 10% to about 20% by weightarginine.

For example, a method described herein may include the concomitantsubcutaneous administration of the first composition and the oraladministration of the tablet or capsule, wherein the patient's levodopaarea under the curve (AUC) from time 0 to the end of the infusion timeis higher as compared to the combination of a patient's levodopa AUCfrom time 0 to the end of the infusion time of a patient who issubcutaneously administered the first composition alone and a patient'slevodopa AUC when a tablet or capsule is administered alone, wherein theamount of levodopa administered concomitantly subcutaneously and orallyis about the same as the combined amount of the levodopa subcutaneouslyalone and orally administered alone.

Also disclosed herein is a method for treatment of a neurological ormovement disorder in a patient in need thereof, said method comprising:subcutaneously administering to the patient, over a subcutaneousinfusion time course of about 7 to about 10 hours or more, a firstpharmaceutically acceptable liquid composition comprising about 6% byweight levodopa and about 0.75% by weight carbidopa to the patient; andorally administering to the patient, before or during the subcutaneousinfusion time course, an immediate release tablet or capsule comprising50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, or 250 mg levodopa, andwherein the immediate release tablet or capsule optionally furthercomprises carbidopa.

Also disclosed herein is a method for treatment of a neurological ormovement disorder in a patient in need thereof, said method comprising:subcutaneously administering to the patient, over a subcutaneousinfusion time course of about 24 hours or more, a first pharmaceuticallyacceptable liquid composition comprising levodopa and carbidopa in anamount to deliver about 720 mg of levodopa and about 90 mg of carbidopato the patient over the course of about 24 hours; and orallyadministering to the patient, before or during the subcutaneous infusiontime course, a tablet or capsule, e.g., an immediate release or modifiedrelease, such as an extended release, tablet or capsule, comprisinglevodopa and carbidopa.

In some embodiments, the method disclosed herein includes administrationof the subcutaneous infusion over the course of about 18 hours at a highactivity rate and over the course of about 6 hours at a low activityrate, wherein about 691.2 mg levodopa and about 86.4 mg carbidopa isadministered over the course of the high activity 18 hours and about28.8 mg levodopa and 3.6 mg carbidopa is administered over the course ofthe low activity 6 hours.

According to some embodiments, the tablet or capsule is orallyadministered substantially concurrently with the start of the infusiontime course. The tablet or capsule may be administered during theinfusion at predefined intervals, or when desired or required, based onfeedback, e.g., for the patient, caregiver, physician, sensors, and thelike. The intervals at which the tablet or capsule are administered maybe substantially the same, or different from one another. According tosome embodiments, a tablet or capsule is orally administered about 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours after the start of the infusiontime course, wherein any number of tablets or capsules may beadministered, as detailed herein. According to some embodiments, thetablet or capsule comprises 100 mg levodopa and 25 mg carbidopa.

According to some embodiments, the first pharmaceutically acceptableliquid composition, which is administered according to the method of theinvention for 24 hours or more, comprises about 6% by weight levodopa,about 0.75% by weight carbidopa, and about 10% to about 20% by weightarginine.

According to some embodiments, whether the first pharmaceuticallyacceptable liquid composition is administered according to the method ofthe invention for 24 hours or more, concomitantly with the oraladministration of a tablet or capsule, as detailed herein, the patient'slevodopa area under the curve (AUC) from time 0 to the end of theinfusion time is higher than that compared to the combination of apatient's levodopa AUC from time 0 to the end of the infusion time whena patient is subcutaneously administered the first composition alonetogether with a patient's levodopa AUC when a tablet or capsule isadministered alone, and when the amount of levodopa administeredconcomitantly subcutaneously and orally is about the same as thecombined amount of the levodopa subcutaneously alone and orallyadministered alone.

Embodiments of the invention are directed to a method for treatment ofParkinson's disease in a patient in need thereof, wherein the methodcomprises:

subcutaneously administering to the patient, over a subcutaneousinfusion time course of about 24 hours or more, a first pharmaceuticallyacceptable liquid composition comprising: levodopa, carbidopa, arginine,and an antioxidant, in an amount to deliver about 720 mg of levodopa andabout 90 mg of carbidopa to the patient over the course of about 24hours; and

orally administering to the patient, before or during the subcutaneousinfusion time course, at least one oral dosage form comprising levodopa.

According to some embodiments, the oral dosage form includes one of:about 50 mg levodopa, about 75 mg levodopa, about 95 mg levodopa, about100 mg levodopa, about 125 mg levodopa, about 145 mg levodopa, about 150mg levodopa, about 195 mg levodopa, about 200 mg levodopa, about 245 mglevodopa, or about 250 mg levodopa.

According to some embodiments, the treatment includes the treatment ofmotor fluctuations. According to further embodiments, the oral dosageform is a morning oral dose.

Further embodiments, of the invention are directed to a method fortreatment of Parkinson's disease, in a patient in need thereof, whereinthe method comprises:

subcutaneously administering to the patient, over a subcutaneousinfusion time course of about 24 hours or more, a first pharmaceuticalcomposition comprising a levodopa moiety and a carbidopa moiety; and,concomitantly,

orally administering to the patient, before or during the subcutaneousinfusion time course, at least one oral dosage form comprising levodopa.

According to some embodiments, the first pharmaceutical compositioncomprises the levodopa moiety and the carbidopa moiety in a ratio ofabout 8:1 w/w.

According to some embodiments, the first pharmaceutical compositioncomprises up to about 720 mg levodopa and up to about 90 mg carbidopa,administered over the course of about 24 hours, wherein the levodopa andcarbidopa are in a ratio of about 8:1 w/w. According to someembodiments, the first pharmaceutical composition comprises about 370 mgto about 720 mg levodopa and about 46 mg to about 90 mg carbidopa,administered over the course of about 24 hours, wherein the levodopa andcarbidopa are in a ratio of about 8:1 w/w.

Additional embodiments of the invention are directed to a method fortreatment of Parkinson's disease in a patient in need thereof, whereinthe method comprises:

subcutaneously administering to the patient, over a subcutaneousinfusion time course of about 24 hours or more, a first pharmaceuticallyacceptable liquid composition comprising: levodopa and carbidopa, in anamount to deliver levodopa and carbidopa in a ratio of about 8:1 w/w tothe patient over the course of about 24 hours; and

orally administering to the patient, before or during the subcutaneousinfusion time course, at least one oral dosage form comprising levodopa.

According to some embodiments, the pharmaceutically acceptable liquidcomposition comprising levodopa and carbidopa, in an amount to deliverabout 370 to about 720 mg of levodopa and about 46 to about 90 mg ofcarbidopa to the patient over the course of about 24 hours.

Some embodiments of the invention are directed to a method for treatmentof Parkinson's disease in a patient in need thereof, wherein the methodcomprises:

subcutaneously administering to the patient, over a subcutaneousinfusion time course of about 24 hours or more, a first pharmaceuticallyacceptable liquid composition comprising: levodopa and carbidopa, in anamount to deliver about 370 to about 720 mg of levodopa and about 46 toabout 90 mg of carbidopa to the patient over the course of about 24hours; and

orally administering to the patient, before or during the subcutaneousinfusion time course, at least one oral dosage form comprising levodopa.

According to some embodiments, the first pharmaceutically acceptableliquid composition comprises levodopa and carbidopa in a ratio of about8:1 w/w.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 provides a graph showing the mean plasma levodopa concentrationof five tested groups vs the time in hours after subcutaneous infusioninitiation; and

FIG. 2 provides a graph showing Cmax carbidopa values obtained from thesubcutaneous administration of three different administered carbidopaconcentrations.

DETAILED DESCRIPTION OF THE INVENTION

The features and other details of the disclosure will now be moreparticularly described. Certain terms employed in the specification,examples, and appended claims are collected here. These definitionsshould be read in light of the remainder of the disclosure andunderstood as by a person of skill in the art. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by a person of ordinary skill in the art.

The terms “treat,” “treatment,” “treating,” and the like are used hereinto generally refer to obtaining a desired pharmacological and/orphysiological effect. The effect may be therapeutic in terms ofpartially or completely curing a disease and/or adverse effectattributed to the disease. The term “treatment” as used herein coversany treatment of a disease in a mammal, particularly a human, andincludes: (a) inhibiting the disease, i.e., preventing the disease fromincreasing in severity or scope; (b) relieving the disease, i.e.,causing partial or complete amelioration of the disease; or (c)preventing relapse of the disease, i.e., preventing the disease fromreturning to an active state following previous successful treatment ofsymptoms of the disease or treatment of the disease.

“Preventing” includes delaying the onset of clinical symptoms,complications, or biochemical indicia of the state, disorder, disease,or condition developing in a subject that may be afflicted with orpredisposed to the state, disorder, disease, or condition but does notyet experience or display clinical or subclinical symptoms of the state,disorder, disease, or condition. “Preventing” includes prophylacticallytreating a state, disorder, disease, or condition in, or developing in,a subject, including prophylactically treating clinical symptoms,complications, or biochemical indicia of the state, disorder, disease,or condition in or developing in a subject.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” as used herein interchangeably refer to any andall solvents, dispersion media, coatings, isotonic and absorptiondelaying agents, and the like, that are compatible with pharmaceuticaladministration.

The terms “pharmaceutical composition” and “pharmaceutical formulation”as used herein refer to a composition or formulation comprising at leastone biologically active compound, for example, levodopa or carbidopa, ora pharmaceutically acceptable salt thereof or a prodrug thereof,formulated together with one or more pharmaceutically acceptableexcipients.

The term “pharmaceutically acceptable salt(s)” as used herein refers tosalts of acidic or basic groups that may be formed with the conjugatesused in the compositions disclosed herein.

“Individual,” “patient,” or “subject” are used interchangeably andinclude any animal, including mammals, mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or non-humanprimates, and humans. In some embodiments, the mammal treated in themethods of the invention is a human suffering from neurodegenerativecondition, such as Parkinson's disease.

The term “about”, as used herein, unless specifically mentionedotherwise, or unless a person skilled in the art would have understoodotherwise, is considered to cover a range of ±10% of the listedvalue(s). It is further noted that any value provided may also beconsidered to cover a range of ±10% of that value, even without the useof the term “about”. This includes the values in the examples section,which may vary according to the utensils and machinery used, the purityof the compounds, etc.

The term “up to” as used herein, unless specifically mentionedotherwise, or unless would have been understood otherwise by a personskilled in the art, when appearing as part of a range, is defined suchthat the range does not include “none”, “nothing”, “0”. That is, if acomponent is an amount of up to a certain amount, e.g., 720 mg, 0 mg isnot considered to be part of the range. Thus, if a compositioncomprises, e.g., up to 360 mg, up to 370 mg, up to 720 mg, of, e.g.,levodopa, the composition must include more than 0 levodopa. Similarly,if a composition comprises, e.g., up to 45 mg, up to 46 mg, up to 90 mg,of, e.g., carbidopa, the composition must comprise more than 0carbidopa.

The term “levodopa moiety”, as used herein, unless specificallymentioned otherwise, or unless would have been understood otherwise by aperson skilled in the art, includes any moiety including levodopa,including, e.g., levodopa itself, a levodopa prodrug, and a levodopasalt. Similarly, the term “carbidopa moiety”, as used herein, unlessspecifically mentioned otherwise, or unless would have been understoodotherwise by a person skilled in the art, includes any moiety includingcarbidopa, including, e.g., carbidopa itself, a carbidopa prodrug, acarbidopa salt.

The term “liquid” as used herein, unless specifically mentionedotherwise, or unless a person skilled in the art would have understoodotherwise, refers to any type of fluid, including gels, aqueous andnon-aqueous compositions, and the like.

The term “concomitant” as used herein, unless specifically mentionedotherwise, or unless a person skilled in the art would have understoodotherwise, refers to any type of combined administration of two or moreactive ingredients, in the same composition, as well as theadministration of those active ingredients at the same time, in separatecompositions, as well as administering the two or more activeingredients sequentially, consecutively, on the same day, with apredefined period of time separating the administration of the activeingredients from one another, and the like. The term “concomitant” mayfurther be used herein to refer to any type of combined administrationof two separate pharmaceutical compositions, wherein each compositionmay be administered in a different administration route, at differenttime intervals, doses, etc. For examples, as detailed herein, onecomposition may be administered parenterally, e.g., subcutaneously,substantially continuously, while a second composition, administeredconcomitantly with the first, by oral administration, in anon-continuous manner Further, the concomitant administration of two ormore separate compositions may be dependent or independent from oneanother.

The terms “continuously” and “substantially continuously” as usedherein, unless specifically mentioned otherwise, or unless a personskilled in the art would have understood otherwise, refer to a period oftime during which a composition is administered over the entire periodof time, with intermissions of less than about 24 hours, about 12 hours,about five hours, about three hours, about one hour, about 30 minutes,about 15 minutes, about five minutes or about one minute. The period oftime during which a composition is administered may be at least aboutsix hours, about eight hours, about 12 hours, about 15 hours, about 18hours, about 21 hours, about 24 hours, three days, seven days, twoweeks, a month, three months, six months, a year, two years, threeyears, five years, ten years, etc.

The term “physiologically acceptable pH value” and the like, as usedherein, unless specifically mentioned otherwise, or unless a personskilled in the art would have understood otherwise, refers to pH valuesin the range of between about 4.5 to about 10. It is further noted thatwhen pH values are provided, including in the examples, the values maybe in the range of about ±0.1 and/or ±10% of the listed value(s), suchthat if the measured pH is 8.1, the same formulation may be prepared toprovide a pH of about 8.0 or 8.2. Such differences may be due totemperature changes, various measuring devices, etc.

A neurological disorder is a disorder of the body's nervous system, andthe term “movement disorder” as used herein refers to a nervous systemcondition that causes abnormal voluntary or involuntary movements, orslow, reduced movements. According to some embodiments, the neurologicalor movement disorder is Parkinson's disease; secondary parkinsonism,such as drug-induced secondary parkinsonism, neuroleptic inducedparkinsonism, postencephalitic parkinsonism, and vascular parkinsonism;motor fluctuations; neurodegenerative disorders; dyskinesia; reduceddopamine levels in the brain; levodopa induced dyskinesia; rapid eyemovement sleep behavior disorder (RBD); dystonia; morning akinesia;tremor symptoms, such as essential tremor and drug-induced tremor;myoclonus; chorea, such as drug induced chorea; tics, such as druginduced tics and organic tics; drug induced movement disorder; druginduced akathisia; restless legs syndrome (RLS); stiff-man syndrome;benign shuddering attacks; malignant neuroleptic syndrome; Huntington'sdisease; Shy-Drager syndrome; brain injury induced conditions, such ascarbon monoxide or manganese intoxication; or any combination thereof.According to some embodiments, the method is directed to treatingParkinson's disease and/or motor fluctuations, including motorfluctuations stemming from Parkinson's disease, motor fluctuations inpatients with Parkinson disease, and the like.

The term “dopa decarboxylase inhibitor” as used herein refers to anagent capable of inhibiting the peripheral metabolism of levodopa todopamine by aromatic L-amino acid decarboxylase, such as carbidopa andbenserazide.

The terms “morning dose” and “morning oral dose” as used herein, unlessspecifically mentioned otherwise, or unless would have been understoodotherwise by a person skilled in the art, are interchangeable and referto an oral dosage form comprising levodopa, which is particularlyadministered in the morning hours, e.g., within 1 minute, 5 minutes, 10minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5hours, 2 hours of the patient's waking time. according to someembodiments, the morning dose refers to an oral dosage form comprisinglevodopa, which is administered within 1 minute, 5 minutes, 10 minutes,15 minutes, 20 minutes, or 30 minutes of the patient's waking hours.

According to some embodiments, the morning oral dose includes one of: 25mg levodopa, 50 mg levodopa, 75 mg levodopa, 95 mg levodopa, 100 mglevodopa, 125 mg levodopa, 145 mg levodopa, 150 mg levodopa, 195 mglevodopa, 200 mg levodopa, 245 mg levodopa, or 250 mg levodopa.

Embodiments of the invention are directed to a method for treatment of aneurological or movement disorder, such as Parkinson's disease, in apatient in need thereof, wherein the method comprises:

parenterally administering a first pharmaceutical compositioncomprising:

-   -   levodopa, a levodopa salt, a levodopa prodrug, or any        combination thereof; and    -   a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI        prodrug, or any combination thereof;

-   and, concomitantly,

orally administering a second pharmaceutical composition comprising:

-   -   levodopa, a levodopa salt, a levodopa prodrug;    -   a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI        prodrug; or any combination thereof.

According to some embodiments, the concomitant administration of thefirst pharmaceutical composition and the second pharmaceuticalcomposition provides a synergistic effect, such that the levodopa bloodlevels obtained by the concomitant administration are higher than theexpected additive effect when providing the first pharmaceuticalcomposition and the second pharmaceutical composition non-concomitantly.According to some embodiments, the synergism between the first andsecond pharmaceutical compositions provides an elevation of betweenabout 5% and about 50% in the levodopa blood levels, in comparison tothe expected additive values. According to some embodiments, thesynergism between the first and second pharmaceutical compositionsprovides an elevation of between about 10% and 40% in the levodopa bloodlevels, between about 15% and 35% in the levodopa blood levels, betweenabout 20% and 40 in the levodopa blood levels, between about 25% and 35%in the levodopa blood levels, or about 20%, 25%, or 30% in the levodopablood levels, in comparison to the expected additive values.

According to some embodiments, the first pharmaceutical compositioncomprises levodopa and carbidopa. According to some embodiments, thesecond pharmaceutical composition comprises levodopa and carbidopa.According to some embodiments, the second pharmaceutical compositioncomprises only levodopa as the active ingredient. According to someembodiments, the second pharmaceutical composition further comprises acatechol o-methyl transferase (COMT) inhibitor, such as entacapone ortolcapone.

According to some embodiments, the first pharmaceutical compositionand/or the second pharmaceutical composition comprise (1) levodopa, alevodopa salt, and/or a levodopa prodrug and/or (2) carbidopa, acarbidopa salt and/or a carbidopa prodrug. According to some embodimentsthe levodopa prodrug is any of the prodrugs disclosed inPCT/IL2020/050960 or U.S. 63/159,236, which are incorporated herein, intheir entirety, by reference. According to some embodiments, thelevodopa prodrug and/or the carbidopa prodrug is any prodrug disclosedin JP 2021-037959.

According to some embodiments, the DDCI is carbidopa, a carbidopaprodrug, a carbidopa salt, benserazide, a benserazide prodrug, abenserazide salt, or any combination thereof. According to someembodiments, the DDCI is carbidopa. The DDCI in the first pharmaceuticalcomposition may be the same or different as the DDCI in the secondpharmaceutical composition. Further, the levodopa moiety in each of thefirst and second pharmaceutical compositions may be the same ordifferent. That is, while according to some embodiments, both the firstpharmaceutical composition and the second pharmaceutical compositioncomprise levodopa, according to other embodiments the firstpharmaceutical composition may comprise one type of levodopa moiety,e.g., a levodopa prodrug and/or a levodopa salt, while the secondpharmaceutical composition comprises a different type of levodopamoiety, e.g., levodopa. It is further noted that the concentration oramount of each moiety within the first pharmaceutical composition may bedifferent than the concentration or amount of that moiety within thesecond pharmaceutical composition.

According to some embodiments the first pharmaceutical composition maybe administered by any parenteral administration route, e.g.,subcutaneously, transdermally, intradermally, intravenously,intramuscularly, intratracheally, intranasally, intrathecally,intragastrically or intraduodenally. According to some embodiments thefirst pharmaceutical composition is administered subcutaneously.According to some embodiments, the first pharmaceutical composition isliquid. According to some embodiments, the first pharmaceuticalcomposition is aqueous.

According to some embodiments, the first pharmaceutical composition isadministered substantially continuously. According to some embodiments,the first pharmaceutical composition is administered subcutaneously viaa designated pump device.

Embodiments of a designated pump may be, for example, any of the pumpembodiments disclosed in U.S. 62/529,784, U.S. 62/576,362,PCT/IB2018/054962, U.S. Ser. No. 16/027,804, U.S. Ser. No. 16/027,710,U.S. Pat. No. 10,463,787, U.S. Pat. No. 10,463,572, U.S. Pat. No.10,603,430, U.S. Ser. No. 16/685,364, US 2020/0093984, USD 29/655,583,USD 29/655,587, USD 29/655,589, USD 29/655,591, USD 29/655,592, USD29/655,594, USD 29/655,597, USD 29/723,714 and U.S. 62/851,903, all ofwhich are incorporated herein by reference in their entirety.

According to some embodiments, the method of the invention comprisesadministering the first pharmaceutical composition at one site, twosites, or three or more sites, wherein the position of the sites may bechanged at any appropriate, possibly pre-determined, intervals. Onceadministered via a specific site, according to some embodiments, theadministration via the same site, or the vicinity of that site, may beonly after a, possibly predefined, period of time. According to someembodiments, the position of any one of the sites is changed after 12,24, 36, 48, 60 or 72 hours. According to some embodiments, the positionof the site is changed after 4, 5, 6 or 7 days. According to someembodiments, the position of the site is changed after two, three orfour weeks. According to some embodiments, the position of the site ischanged when required or desired, e.g., according to subjective datareceived from the patient and/or according to objective data received,e.g., from sensors located at, or in the vicinity of, the injectionsite(s).

According to some embodiments, the administrated volume and/or theadministration rate is identical in all or at least two of the sites.According to other embodiments, the administration rate and/oradministrated volume differ from site to site. Each site may becontrolled independently or otherwise, all sites may be controlleddependently on one another.

According to some embodiments, the method of the invention comprisessubcutaneously administrating the first pharmaceutical composition ofthe invention over the course of about 5 to about 24 hours or more, forexample, from about 5 to about 12 hours or more, from about 7 to about10 hours or more, or for example, about 8 hours or about 24 hours.

According to some embodiments, the dose of the carbidopa moiety in thefirst pharmaceutical composition is between about 10 mg and about 25 mgper administration, between about 10 mg and about 50 mg peradministration, between about 10 mg and about 75 mg per administration,between about 12 mg and about 25 mg per administration, between about 12mg and about 50 mg per administration, between about 12 mg and about 75mg per administration, between about 15 mg and about 25 mg peradministration, between about 15 mg and about 50 mg per administration,between about 15 mg and about 75 mg per administration, between about 25mg and about 50 mg per administration, between about 25 mg and about 75mg per administration, between about 50 mg and about 75 mg peradministration. According to some embodiments, the dose of the carbidopamoiety in the first pharmaceutical composition is about 90 mg, forexample, administered over the course of about 5 to about 24 hours ormore. According to some embodiments, the dose of the carbidopa moiety inthe first pharmaceutical composition is between about 46 mg and about 90mg per administration. According to some embodiments, the dose of thecarbidopa moiety in the first pharmaceutical composition is about 90 mg,for example, administered over the course of about 24 hours. Accordingto some embodiments, the dose of the carbidopa moiety in the firstpharmaceutical composition is between about 46 mg to about 90 mg, forexample, administered over the course of about 24 hours.

According to some embodiments, the dose of the levodopa moiety in thefirst pharmaceutical composition is between about 10 mg and about 800 mgper administration, between about 10 mg and about 25 mg peradministration, between about 25 mg and about 50 mg per administration,between about 50 mg and about 75 mg per administration, between about 75mg and about 100 mg per administration, between about 100 mg and about150 mg per administration, between about 150 mg and about 200 mg peradministration, between about 200 mg and about 250 mg peradministration, between about 250 mg and about 300 mg peradministration, between about 300 mg and about 350 mg peradministration, between about 350 mg and about 400 mg peradministration, between about 400 mg and about 450 mg peradministration, between about 450 mg and about 500 mg peradministration, between about 500 mg and 800 mg, between about 600 mgand about 800 mg, between about 700 mg and about 800 mg, or about 720mg. In certain embodiments, the dose of the levodopa moiety in the firstpharmaceutical composition is between about 370 mg to about 720 mg. Incertain embodiments, the dose is administered over the course of about 5to about 24 (e.g., about 7 to about 10, or about 8 hours, or about 24hours) hours or more. According to some embodiments, the dose of thelevodopa moiety in the first pharmaceutical composition is about 720 mg,for example, administered over the course of about 24 hours. Accordingto some embodiments, the dose of the levodopa moiety in the firstpharmaceutical composition is between about 370 mg about 720 mg, forexample, administered over the course of about 24 hours. According tosome embodiments, the dose of the levodopa moiety in the firstpharmaceutical composition is between about 360 mg about 720 mg, forexample, administered over the course of about 24 hours. According tosome embodiments, the dose of the levodopa moiety in the firstpharmaceutical composition is about 720 mg at the most.

In certain embodiments, the first pharmaceutical composition isadministered in an amount to deliver from about 100 to about 200 mg oflevodopa and about 12 to about 50 mg of carbidopa to the patient. Incertain embodiments, the first pharmaceutical composition isadministered in an amount to deliver from about 140 to about 170 mg oflevodopa and about 16 to about 24 mg of carbidopa to the patient. Incertain embodiments, the dose is administered over the course of about 5to about 24 (e.g., about 7 to about 10) hours or more. In certainembodiments, the first pharmaceutical composition is administered in anamount to deliver from about 650 mg to about 800 mg, e.g., about 720 mgof levodopa and about 80 mg to about 100 mg, e.g., about 90 mg,carbidopa to the patient over the course of about 24 hours. According tosome embodiments, the dose of the carbidopa moiety in the firstpharmaceutical composition is between about 46 mg about 90 mg, forexample, administered over the course of about 24 hours. According tosome embodiments, the dose of the carbidopa moiety in the firstpharmaceutical composition is between about 45 mg about 90 mg, forexample, administered over the course of about 24 hours. According tosome embodiments, the dose of the carbidopa moiety in the firstpharmaceutical composition is about 90 mg at the most.

According to some embodiments, the first pharmaceutical compositioncomprises levodopa and carbidopa in a ratio of about 8:1 w/w. Accordingto some embodiments, the first pharmaceutical composition isadministered in an amount to deliver about 720 mg LD and about 90 mg CDper day, about 360 mg LD and about 45 mg CD per day, about 370 mg LD andabout 46 mg CD per day, wherein the levodopa and carbidopa are in aratio of about 8:1 w/w.

According to some embodiments, the first pharmaceutical composition isadministered in an amount to deliver more than 0 mg and up to about 720mg LD and more than 0 mg and up to about 90 mg CD per day, wherein theratio of LD/CD administered is about 8:1 w/w. According to someembodiments, the first pharmaceutical composition is administered in anamount to deliver between about 8 mg to about 720 mg LD and about 1 mgto about 90 mg CD per day, at a ratio of about 8:1 w/w LD/CD. Accordingto some embodiments, the first pharmaceutical composition isadministered in an amount to deliver between about 360 mg to about 720mg LD and about 45 mg to about 90 mg CD per day, at a ratio of about 8:1w/w LD/CD. According to some embodiments, the first pharmaceuticalcomposition is administered in an amount to deliver between about 370 mgto about 720 mg LD and about 46 mg to about 90 mg CD per day, at a ratioof about 8:1 w/w LD/CD. According to some embodiments, the firstpharmaceutical composition is administered in an amount to deliverbetween about 370 mg to about 720 mg LD and about 46 mg to about 90 mgCD per day, at a ratio of about 8:1 w/w LD/CD.

According to some embodiments, the first pharmaceutical compositioncomprises up to about 720 mg levodopa. According to some embodiments,the first pharmaceutical composition comprises up to about 90 mgcarbidopa. According to some embodiments, the first pharmaceuticalcomposition comprises up to about 720 mg levodopa and up to about 90 mgcarbidopa, wherein the levodopa and carbidopa and in a ratio of about8:1 w/w.

According to some embodiments, the first pharmaceutical composition isadministered in an amount to deliver about 720 mg, about 660-670 mg,about 620-630 mg, about 560-570 mg, about 510-520 mg, about 470-480 mg,about 410-420 mg, or about 370-380 mg of levodopa per day. According tosome embodiments, the first pharmaceutical composition is administeredin an amount to deliver about 90 mg, about 85-90 about 80-85 mg, about75-80 mg, about 70-75 mg, about 65-70 mg, about 60-65, about 55-60 mg,about 50-55 mg, or about 45-50 mg of carbidopa per day. According tosome embodiments, the first pharmaceutical composition is administeredin an amount to deliver about 720 mg levodopa and about 90 mg carbidopa,about 660-670 mg levodopa and about 80-85 mg carbidopa, about 610-620 mglevodopa and about 75-80 mg carbidopa, about 560-570 mg levodopa andabout 70-75 mg carbidopa, about 510-520 mg levodopa and about 60-70 mgcarbidopa, about 470-480 mg levodopa and about 55-60 mg carbidopa, about410-420 mg levodopa and about 50-55 mg carbidopa, or about 370-380 mg oflevodopa and about 45-50 mg carbidopa per day, wherein the levodopa andcarbidopa are administered at a ratio of about 8:1 w/w.

According to some embodiments, the first pharmaceutical compositioncomprises a levodopa moiety and a carbidopa moiety in a ratio of betweenabout 2:1 w/w to about 40:1 w/w. According to some embodiments, thefirst pharmaceutical composition comprises a levodopa moiety and acarbidopa moiety in a ratio of between about 2:1 w/w to about 4:1 w/w.According to some embodiments, the first pharmaceutical compositioncomprises a levodopa moiety and a carbidopa moiety in a ratio of betweenabout 4:1 w/w to about 6:1 w/w. According to some embodiments, the firstpharmaceutical composition comprises a levodopa moiety and a carbidopamoiety in a ratio of between about 6:1 w/w to about 8:1 w/w. Accordingto some embodiments, the first pharmaceutical composition comprises alevodopa moiety and a carbidopa moiety in a ratio of between about 8:1w/w to about 10:1 w/w. According to some embodiments, the firstpharmaceutical composition comprises a levodopa moiety and a carbidopamoiety in a ratio of between about 10:1 w/w to about 15:1 w/w. Accordingto some embodiments, the first pharmaceutical composition comprises alevodopa moiety and a carbidopa moiety in a ratio of between about 15:1w/w to about 20:1 w/w. According to some embodiments, the firstpharmaceutical composition comprises a levodopa moiety and a carbidopamoiety in a ratio of between about 20:1 w/w to about 25:1 w/w. Accordingto some embodiments, the first pharmaceutical composition comprises alevodopa moiety and a carbidopa moiety in a ratio of between about 25:1w/w to about 30:1 w/w. According to some embodiments, the firstpharmaceutical composition comprises a levodopa moiety and a carbidopamoiety in a ratio of between about 30:1 w/w to about 35:1 w/w. Accordingto some embodiments, the first pharmaceutical composition comprises alevodopa moiety and a carbidopa moiety in a ratio of between about 35:1w/w to about 40:1 w/w. According to some embodiments, the firstpharmaceutical composition comprises a levodopa moiety and a carbidopamoiety in a ratio of about 20:1 w/w.

According to some embodiments, the first pharmaceutical composition isadministered in an amount to deliver about 100 mg, about 200 mg, about240 mg, about 480 mg, about 720 mg, about 960 mg, about 1200 mg, about1440 mg, about 1680 mg, about 1920 mg, about 2160 mg, about 2400 mg,about 2640 mg, about 2880 mg, about 3120 mg, about 3360 mg, about 3600mg, about 3840 mg, about 4080 mg, about 4320 mg, about 4560 mg, about4800 mg, about 5040 mg, about 5280 mg, about 5520 mg, about 5760 mg,about 6000 mg, of a levodopa moiety over the course of about 24 hours.According to some embodiment the first pharmaceutical composition isadministered in an amount to deliver between about 100 mg to about 6000mg of a levodopa moiety over the course of about 24 hours. According tosome embodiment the first pharmaceutical composition is administered inan amount to deliver between about 240 mg to about 4800 mg of a levodopamoiety over the course of about 24 hours. According to some embodimentthe first pharmaceutical composition is administered in an amount todeliver between about 8 mg to about 1600 mg of a levodopa moiety overthe course of about 24 hours. According to some embodiment the firstpharmaceutical composition is administered in an amount to deliverbetween about 8 mg to about 3200 mg of a levodopa moiety over the courseof about 24 hours. According to some embodiment the first pharmaceuticalcomposition is administered in an amount to deliver between about 8 mgto about 3440 mg of a levodopa moiety over the course of about 24 hours.

According to some embodiments, the first pharmaceutical composition isadministered in an amount to deliver about 5 mg, about 6 mg, about 10mg, about 12 mg, about 24 mg, about 36 mg, about 48 mg, about 60 mg,about 72 mg, about 84 mg, about 96 mg, about 108 mg, about 120 mg, about132 mg, about 144 mg, about 156 mg, about 168 mg, about 180 mg, about192 mg, about 204 mg, about 216 mg, about 228 mg, about 240 mg, about252 mg, about 264 mg, about 276 mg, about 288 mg, or about 300 mg of acarbidopa moiety over the course of about 24 hours. According to someembodiments, the first pharmaceutical composition is administered in anamount to deliver between about 12 mg to about 240 mg of a carbidopamoiety over the course of about 24 hours. According to some embodiments,the first pharmaceutical composition is administered in an amount todeliver between about 1 mg to about 300 mg of a carbidopa moiety overthe course of about 24 hours.

According to some embodiment the first pharmaceutical composition isadministered in an amount to deliver between about 240 mg to about 4800mg of a levodopa moiety and between about 12 mg to about 240 mg of acarbidopa moiety over the course of about 24 hours.

According to some embodiments, the method of the invention comprisessubcutaneously administrating between about 1 to about 30 ml of thefirst pharmaceutical composition of the invention over the course of 24hours. According to some embodiments, the method of the inventioncomprises subcutaneously administrating between about 1 to about 120 mlof the first pharmaceutical composition of the invention over the courseof 24 hours. According to some embodiments, the method of inventioncomprises subcutaneously administrating between about 1 ml to about 2ml, between about 2 ml to about 3 ml, between about 3 ml to about 4 ml,between about 4 ml to about 5 ml, between about 5 ml to about 6 ml,between about 6 ml to about 7 ml, between about 7 ml to about 8 ml,between about 8 ml to about 9 ml, between about 9 ml to about 10 ml,between about 10 ml to about 11ml, between about 11 ml to about 12 ml,between about 12 ml to about 13 ml, between about 13 ml to about 14 ml,between about 14 ml to about 15 ml between about 15 ml to about 16 ml,between about 16 ml to about 17 ml, between about 17 ml to about 18 ml,between about 18 ml to about 19 ml, between about 19 ml to about 20 ml,between about 20 ml to about 21 ml, between about 21 ml to about 22 ml,between about 22 ml to about 23 ml, between about 23 ml to about 24 ml,between about 24 ml to about 25 ml, between about 25 ml to about 26 ml,between about 26 ml to about 27 ml, between about 27 ml to about 28 ml,between about 28 ml to about 29 ml, between about 29 ml to about 30 ml,between about 30 ml to about 40 ml, between about 40 ml to about 50 ml,between about 50 ml to about 60 ml, between about 60 ml to about 70 ml,between about 70 ml to about 80 ml, between about 80 ml to about 90 ml,between about 90 ml to about 100 ml, between about 100 ml to about 110ml, between about 110 ml to about 120 ml, of the first pharmaceuticalcomposition over the course of 24 hours. According to some embodiments,the method of the invention comprises subcutaneously administratingabout 12 ml of the first pharmaceutical composition of the inventionover the course of about 24 hours. According to some embodiments, themethod of the invention comprises subcutaneously administrating about 20ml of the first pharmaceutical composition of the invention over thecourse of about 24 hours. According to some embodiments, the method ofthe invention comprises subcutaneously administrating up to about 12 mlof the first pharmaceutical composition of the invention over the courseof about 24 hours. According to some embodiments, the method of theinvention comprises subcutaneously administrating up to about 20 ml ofthe first pharmaceutical composition of the invention over the course ofabout 24 hours. According to some embodiments, the method of theinvention comprises subcutaneously administrating up to about 120 ml ofthe first pharmaceutical composition of the invention over the course ofabout 24 hours.

According to some embodiments, the first pharmaceutical composition isadministered at a volume of between about 1 ml to about 30 ml per siteper day, between about 2 ml to about 20 ml per site per day, betweenabout 3 ml to about 10 ml per site per day, between about 5 ml to about7 ml per site per day, or about 6 ml per site per day.

According to some embodiments, the first pharmaceutical composition isadministered at a volume of between about 1 ml to about 2.5 ml per siteper day, between about 2.5 ml to about 5.0 ml per site per day, betweenabout 5.0 ml to about 7.5 ml per site per day, between about 7.5 ml toabout 10 ml per site per day, between about 10 ml to about 12.5 ml persite per day, between about 12.5 ml to about 15 ml per site per day,between about 15 ml to about 17.5 ml per site per day, between about17.5 ml to about 20 ml per site per day, between about 20 ml to about22.5 ml per site per day, between about 22.5 ml to about 25 ml per siteper day, between about 25 ml to about 27.5 ml per site per day, betweenabout 27.5 ml to about 30 ml per site per day. According to someembodiments, the first pharmaceutical composition is administered at avolume of about 6 ml per site per day.

It is noted that the administration rate may be constant over the courseof 24 hours or may change over the course of 24 hours. For instance,according to some embodiments, there may be a certain rate for highactivity/day hours and a different rate for low activity/night hours.The high activity/day hours may be, e.g., about 15, about 16, about 17,about 18 or about 19 hours, while the low activity night hours may beabout 9, about 8, about 7, about 6 or about 5 hours, respectively.According to some embodiments, the high activity/day rate is implementedfor about 18 hours, while the low activity/night rate is implemented forabout 6 hours. According to some embodiments, the high activity/day rateis implemented for about 16 hours, while the low activity/night rate isimplemented for about 8 hours. According to some embodiments, theadministration rate is at least partially determined by input receivedfrom the patient, a caregiver, at least one sensor and the like.According to some embodiments, the administration rate may be elevatedwhen necessary or decreased when necessary according to a predefinedpattern that may be set periodically, e.g., by a caregiver or thepatient. According to other embodiments, the administration rate may bealtered, e.g., elevated or decreased, in an on-line manner, for example,according input received from the patient, a caregiver, or at least onesensor, indicating that a change in administration rate is required orbeneficial. For instance, if the patient wishes to rest at a certainpoint during the day, the rate may be decreased from day to night rate,e.g., by a command provided by the patient. In addition, a caregiver maygive a command to the system in view of the patient, e.g., restingduring the day. Further, a sensor may alert the system that the patienthas gone to sleep (or fallen asleep) and decrease the administrationrate accordingly. Sensors may also provide sleep pattern data, allowingthe system to be notified in advance of the patient awaking from sleep,and in response, e.g., elevating the administration rate. The patient'smonitored condition may also cause the administration rate to bealtered, e.g., lapsing into an “off episode” and the like, may cause theadministration rate to be raised.

The administration rate may be between about 0.01 mL/site/hour to about1 mL/site/hour. According to some embodiments, the administration rateis between about 0.01-0.02 mL/site/hour. According to some embodiments,the administration rate is between about 0.02-0.03 mL/site/hour.According to some embodiments, the administration rate is between about0.03-0.04 mL/site/hour. According to some embodiments, theadministration rate is between about 0.04-0.05 mL/site/hour. Accordingto some embodiments, the administration rate is between about 0.05-0.06mL/site/hour. According to some embodiments, the administration rate isbetween about 0.06-0.07 mL/site/hour. According to some embodiments, theadministration rate is between about 0.07-0.08 mL/site/hour. Accordingto some embodiments, the administration rate is between about 0.08-0.09mL/site/hour. According to some embodiments, the administration rate isbetween about 0.09-0.1 mL/site/hour. According to some embodiments, theadministration rate is between about 0.1-0.15 mL/site/hour. According tosome embodiments, the administration rate is between about 0.15-0.2mL/site/hour. According to some embodiments, the administration rate isbetween about 0.2-0.25 mL/site/hour. According to some embodiments, theadministration rate is between about 0.25-0.3 mL/site/hour. According tosome embodiments, the administration rate is between about 0.3-0.35mL/site/hour. According to some embodiments, the administration rate isbetween about 0.35-0.4 mL/site/hour. According to some embodiments, theadministration rate is between about 0.4-0.45 mL/site/hour. According tosome embodiments, the administration rate is between about 0.45-0.5mL/site/hour. According to some embodiments, the administration rate isbetween about 0.5-0.55 mL/site/hour. According to some embodiments, theadministration rate is between about 0.55-0.6 mL/site/hour. According tosome embodiments, the administration rate is between about 0.6-0.65mL/site/hour. According to some embodiments, the administration rate isbetween about 0.65-0.7 mL/site/hour. According to some embodiments, theadministration rate is between about 0.7-0.75 mL/site/hour. According tosome embodiments, the administration rate is between about 0.75-0.8mL/site/hour. According to some embodiments, the administration rate isbetween about 0.8-0.85 mL/site/hour. According to some embodiments, theadministration rate is between about 0.85-0.9 mL/site/hour. According tosome embodiments, the administration rate is between about 0.9-0.95mL/site/hour. According to some embodiments, the administration rate isbetween about 0.95-1.0 mL/site/hour.

According to some embodiments, the administration rate in the lowactivity/night hours is between about 0.01-0.15 mL/site/hour. Accordingto some embodiments, the administration rate in the low activity/nighthours is between about 0.01-0.02 mL/site/hour. According to someembodiments, the administration rate in the low activity/night hours isbetween about 0.02-0.03 mL/site/hour. According to some embodiments, theadministration rate in the low activity/night hours is between about0.03-0.04 mL/site/hour. According to some embodiments, theadministration rate in the low activity/night hours is between about0.04-0.05 mL/site/hour. According to some embodiments, theadministration rate in the low activity/night hours is between about0.05-0.06 mL/site/hour. According to some embodiments, theadministration rate in the low activity/night hours is between about0.06-0.07 mL/site/hour. According to some embodiments, theadministration rate in the low activity/night hours is between about0.07-0.08 mL/site/hour. According to some embodiments, theadministration rate in the low activity/night hours is between about0.08-0.09 mL/site/hour. According to some embodiments, theadministration rate in the low activity/night hours is between about0.09-0.1 mL/site/hour. According to some embodiments, the administrationrate in the low activity/night hours is between about 0.1-0.11mL/site/hour. According to some embodiments, the administration rate inthe low activity/night hours is between about 0.11-0.12 mL/site/hour.According to some embodiments, the administration rate in the lowactivity/night hours is between about 0.12-0.13 mL/site/hour. Accordingto some embodiments, the administration rate in the low activity/nighthours is between about 0.13-0.14 mL/site/hour. According to someembodiments, the administration rate in the low activity/night hours isbetween about 0.14-0.15 mL/site/hour. According to some embodiments, theadministration rate in the low activity/night hours is about 0.04mL/site/hour. According to some embodiments, the administration rate inthe low activity/night hours is about 0.08 mL/site/hour.

According to some embodiments, the administration rate in the highactivity/day hours is between about 0.15-1.0 mL/site/hour. According tosome embodiments, the administration rate in the high activity/day hoursis between about 0.15-0.2 mL/site/hour. According to some embodiments,the administration rate in the high activity/day hours is between about0.2-0.25 mL/site/hour. According to some embodiments, the administrationrate in the high activity/day hours is between about 0.25-0.3mL/site/hour. According to some embodiments, the administration rate inthe high activity/day hours is between about 0.3-0.35 mL/site/hour.According to some embodiments, the administration rate in the highactivity/day hours is between about 0.35-0.4 mL/site/hour. According tosome embodiments, the administration rate in the high activity/day hoursis between about 0.4-0.45 mL/site/hour. According to some embodiments,the administration rate in the high activity/day hours is between about0.45-0.5 mL/site/hour. According to some embodiments, the administrationrate in the high activity/day hours is between about 0.5-0.55mL/site/hour. According to some embodiments, the administration rate inthe high activity/day hours is between about 0.55-0.6 mL/site/hour.According to some embodiments, the administration rate in the highactivity/day hours is between about 0.6-0.65 mL/site/hour. According tosome embodiments, the administration rate in the high activity/day hoursis between about 0.65-0.7 mL/site/hour. According to some embodiments,the administration rate in the high activity/day hours is between about0.7-0.75 mL/site/hour. According to some embodiments, the administrationrate in the high activity/day hours is between about 0.75-0.8mL/site/hour. According to some embodiments, the administration rate inthe high activity/day hours is between about 0.8-0.85 mL/site/hour.According to some embodiments, the administration rate in the highactivity/day hours is between about 0.85-0.9 mL/site/hour. According tosome embodiments, the administration rate in the high activity/day hoursis between about 0.9-0.95 mL/site/hour. According to some embodiments,the administration rate in the high activity/day hours is between about0.95-1.0 mL/site/hour. According to some embodiments, the administrationrate in the high activity/day hours is about 0.32 mL/site/hour.According to some embodiments, the administration rate in the highactivity/day hours is between about 0.32 mL/hour and about 0.64 mL/hour.According to some embodiments, the administration rate in the highactivity/day hours is about 0.64 mL/hour, about 0.59 mL/hour, about 0.55mL/hour, about 0.5 mL/hour, about 0.45 mL/hour, about 0.41 mL/hour,about 0.36 mL/hour, or about 0.32 mL/hour.

As mentioned above, while the low and high rates are referred to asnight and day rates, respectively, they may be used irrespective of thetime of day; rather, of the condition of the patient and the like, e.g.,low activity and high activity. Further, the rate may be alteredgradually, and may be set at any appropriate value, not necessarilybound to one particular high rate and one particular low rate.

According to some embodiments, the first composition is administeredover the course of about 12 to about 20 hours (e.g., about 18 hours) ata high activity rate and about 4 to about 12 hours (e.g., about 6 hours)at a low activity rate, wherein about 500 mg to about 800 mg (e.g.,about 700 mg or about 691.2 mg) levodopa and about 60 mg to about 100 mg(e.g., about 80 mg or about 86.4 mg) is administered over the course ofthe high activity and about 20 mg to about 40 mg (e.g., about 30 mg orabout 28.8 mg) levodopa and about 2 mg to about 5 mg (e.g., about 3 mgor about 3.6 mg) carbidopa is administered over the course of the lowactivity. According to some embodiments, the high activity rate and/orthe low activity rate may be a consecutive time period in the course of24 hours. According to other embodiments, the high activity rate and/orthe low activity rate may be administered at several, non-consecutivetime periods over the course of 24 hours.

It is further noted that the administrated volume and/or administrationrate may be constant throughout the treatment, or may vary duringdifferent hours of the day, between different days, weeks or months oftreatment, and the like. According to some embodiments, the patient ismonitored, e.g., independently, by a caretaker, or electronically, e.g.,by sensors, possibly found in a dedicated device, e.g., a watch-likedevice, patch-like sensor, the administration pump, and the like.According to such embodiments, the administration volume and/or rate aredetermined according to data received from such monitoring.

Some embodiments are directed to a method for administering a bolussubcutaneous injection of the first pharmaceutical composition of theinvention. According to some embodiments, the bolus injection comprisesbetween about 0.5 to about 2.0 mL/Kg of the first pharmaceuticalcomposition. According to some embodiments, the bolus injectioncomprises between about 0.5 to about 0.75 mL/Kg of the firstpharmaceutical composition. According to some embodiments, the bolusinjection comprises between about 0.75 to about 1.0 mL/Kg of the firstpharmaceutical composition. According to some embodiments, the bolusinjection comprises between about 1.0 to about 1.25 mL/Kg of the firstpharmaceutical composition. According to some embodiments, the bolusinjection comprises between about 1.25 to about 1.5 mL/Kg of the firstpharmaceutical composition. According to some embodiments, the bolusinjection comprises between about 1.5 to about 1.75 mL/Kg of the firstpharmaceutical composition. According to some embodiments, the bolusinjection comprises between about 1.75 to about 2.0 mL/Kg of the firstpharmaceutical composition. According to some embodiments, the bolusinjection comprises between about 0.75 to about 1.25 mL/Kg of the firstpharmaceutical composition. According to some embodiments, the bolusinjection comprises about 1.0 mL/Kg of the first pharmaceuticalcomposition.

The bolus subcutaneous injection may be administered at any time pointin relation to any possible continuous subcutaneous administrations,e.g., prior to, during, or after the continuous administration. Thebolus subcutaneous injection may be administered at any time pointduring the day. The bolus subcutaneous injection may be administeredonce a day, once every two, three, four five or six days, once a week,or more. The bolus subcutaneous injection may be administered whenrequired/desired, according to feedback received from the patient,caretaker, physician, sensors, and the like, and/or according to apredefined regimen. The bolus subcutaneous injection may be administeredover between about five minutes to about 40 minutes, between about fiveminutes to about 10 minutes, between about 10 minutes to 15 minutes,between about 15 minutes to 20 minutes, between about 20 minutes to 25minutes, between about 25 minutes to 30 minutes, between about 30minutes to 35 minutes, between about 35 minutes to 40 minutes.

According to some embodiments, the administered dose may be doubled,tripled or more, by using more than one pump, more than one injectionsite for each pump, and the like.

According to some embodiments, the first pharmaceutical composition isadministered for a defined period of time, e.g., days, weeks, months, oryears. According to some embodiments, the first pharmaceuticalcomposition is administered endlessly, for the treatment of a chroniccondition.

According to some embodiments, the first pharmaceutical compositioncomprises between about 1% w/v and about 40% w/v of levodopa, a levodopaprodrug, a levodopa salt, or any combination thereof. According to someembodiments, the first pharmaceutical composition comprises betweenabout 1% w/v and about 5% w/v, between about 5% w/v and about 10% w/v,between about 10% w/v and about 15% w/v, between about 15% w/v and about20% w/v, between about 20% w/v and about 25% w/v, between about 25% w/vand about 30% w/v, between about 30% w/v and about 35% w/v, betweenabout 35% w/v and about 40% w/v, between about 2% w/v and about 10% w/v,between about 4% w/v and about 8% w/v, between about 5% w/v and about 7%w/v, about 6% w/v of levodopa, a levodopa prodrug, a levodopa salt, orany combination thereof.

According to some embodiments, the first pharmaceutical compositioncomprises between about 0.5% w/v and about 10% w/v of carbidopa, acarbidopa salt, a carbidopa prodrug, or any combination thereof.According to some embodiments, the first pharmaceutical compositioncomprises between about 0.5% w/v and about 1% w/v, between about 1% w/vand about 1.5% w/v, between about 1.5% w/v and about 2% w/v, betweenabout 2% w/v and about 2.5% w/v, between about 2.5% w/v and about 3%w/v, between about 3% w/v and about 3.5% w/v, between about 3.5% w/v andabout 4% w/v, between about 4% w/v and about 4.5% w/v, between about4.5% w/v and about 5% w/v, between about 5% w/v and about 5.5% w/v,between about 5.5% w/v and about 6% w/v, between about 6% w/v and about6.5% w/v, between about 6.5% w/v and about 7% w/v, between about 7% w/vand about 7.5% w/v, between about 7.5% w/v and about 8% w/v, betweenabout 8% w/v and about 8.5% w/v, between about 8.5% w/v and about 9%w/v, between about 9% w/v and about 9.5% w/v, between about 9.5% w/v andabout 10% w/v, about 0.75% w/v of carbidopa, a carbidopa salt, acarbidopa prodrug, or any combination thereof.

For example, provided herein is a first pharmaceutical compositionsuitable for parenteral (e.g., subcutaneous) administration, includesabout 4-10% by weight levodopa, about 0.5 to about 2% by weightcarbidopa, and about 10% to about 20% by weight arginine. Anotherexemplary first pharmaceutical composition provided herein includesabout 6% by weight levodopa, about 0.75% by weight carbidopa, and about10% to about 20% by weight arginine.

According to some embodiments, the first pharmaceutical compositioncomprises between about 0.05% w/v and about 2.0% w/v, between about0.05% w/v and about 0.1% w/v, between about 0.1% w/v and about 0.2% w/v,between about 0.2% w/v and about 0.3% w/v, between about 0.3% w/v andabout 0.4% w/v, between about 0.4% w/v and about 0.5% w/v, between about0.5% w/v and about 0.6% w/v, between about 0.6% w/v and about 0.7% w/v,between about 0.7% w/v and about 0.8% w/v, between about 0.8% w/v andabout 0.9% w/v, between about 0.9% w/v and about 1.0% w/v, between about1% w/v and about 1.1% w/v, between about 1.1% w/v and about 1.2% w/v,between about 1.2% w/v and about 1.3% w/v, between about 1.3% w/v andabout 1.4% w/v, between about 1.4% w/v and about 1.5% w/v, between about1.5% w/v and about 1.6% w/v, between about 1.6% w/v and about 1.7% w/v,between about 1.7% w/v and about 1.8% w/v, between about 1.8% w/v andabout 1.9% w/v, between about 1.9% w/v and about 2.0% w/v, between about0.75% w/v and about 1.25% w/v, about 0.75% w/v, about 0.8% w/v, about0.85% w/v, about 0.9% w/v, about 0.95% w/v, about 1.0% w/v of anantioxidant or a combination of antioxidants.

According to some embodiments, the antioxidant is selected from thegroup consisting of ascorbic acid or a salt thereof, a cysteine, such asN-acetyl cysteine, a bisulfite or a salt thereof, glutathione, atyrosinase inhibitor, a bivalent cation, butylated hydroxy toluene(BHT), beta hydroxy acid (BHA) tocopherol, gentisic acid, tocopherol,tocopherol derivative, thioglycerol, and any combination thereof.According to some embodiments, the antioxidant is ascorbic acid.According to some embodiments, the antioxidant is N-acetyl cysteine(NAC). According to some embodiments, the first pharmaceuticalcomposition comprises a combination of ascorbic acid and NAC. Forexample, provided herein is a first pharmaceutical composition, suitablefor e.g., subcutaneous administration, that includes about 0.1% to about10% by weight ascorbic acid or a pharmaceutically acceptable saltthereof, about 0.01% to about 1% by weight of a component selected fromthe group consisting of: NAC, L-cysteine and pharmaceutically acceptablesalts thereof; about 2% to about 16% by weight levodopa or an esterthereof; and about 0.6% to about 2% by weight carbidopa or an esterthereof.

According to some embodiments, the first pharmaceutical compositioncomprises a base. According to some embodiments the base is selectedfrom the group consisting of arginine, NaOH,tris(hydroxymethyl)aminomethane (TRIS), NH₄OH, ethylenediamine,diethylamine, ethanolamine, diethanolamine, meglumine, and anycombination thereof. According to some embodiments, the base isarginine.

According to some embodiments, the first pharmaceutical compositioncomprises between about 5% w/v and about 30% w/v or a base. According tosome embodiments, the first pharmaceutical composition comprises betweenabout 5% w/v and about 10% w/v, between about 10% w/v and about 15% w/v,between about 15% w/v and about 20% w/v, between about 20% w/v and about25% w/v, between about 25% w/v and about 30% w/v, between about 12.5%w/v and 17.5% w/v, or about 15% w/v, or about 15.2% w/v base.

According to some embodiments, the first pharmaceutical compositioncomprises a surfactant. According to some embodiments, the surfactant isselected from Tween-80, Tween-60, Tween-40, Tween-20, Tween-65,Tween-85, Span 20, Span 40, Span 60, Span 80, Span 85, polyoxyl 35castor oil (Cremophor EL), polyoxyethylene-660-hydroxystearate (macrogol660), or Poloxamer 188 (Pluronic® F-68), or any combination thereof. Thefirst pharmaceutical composition of the invention may include betweenabout 0.1 to about 3.0% w/v of a surfactant or combination of two ormore surfactants. According to some embodiments, the firstpharmaceutical composition comprises between about 0.1 to about 0.2%w/v, between about 0.2 to about 0.3% w/v, between about 0.3 to about0.4% w/v, between about 0.4 to about 0.5% w/v, between about 0.5 toabout 0.6% w/v, between about 0.6 to about 0.7% w/v, between about 0.7to about 0.8% w/v, between about 0.8 to about 0.9% w/v, between about0.9 to about 1.0% w/v, between about 1.0 to about 1.5% w/v, betweenabout 1.5 to about 2.0% w/v, between about 2.0 to about 2.5% w/v,between about 2.5 to about 3.0% w/v of a surfactant or combination oftwo or more surfactants.

The first pharmaceutical composition may further comprise an additionalpharmaceutically acceptable excipient, such as N-methylpyrrolidone(NMP), polyvinylpyrrolidone (PVP), propylene glycol, a preservative, apharmaceutically acceptable vehicle, a stabilizer, a dispersing agent, asuspending agent, an amino sugar, a calcium chelator, proteaseinhibitors, or any combination thereof. The first pharmaceuticalcomposition of the invention may comprise between about 5.0 to about80.0% w/v or an additional pharmaceutically acceptable excipient, e.g.,a solvent, such as NMP or a buffer or any other co-solvent. For example,provided here in, is a pharmaceutically acceptable first compositionthat includes about 6% by weight levodopa, about 0.75% by weightcarbidopa, about 10% to about 20% by weight arginine, about 0.5% byweight of L-cysteine or NAC, and/or about 0.5% by weight ascorbic acidor a salt thereof. An exemplary pharmaceutical first composition (e.g.,formulation A) may include about 6% by weight levodopa, about 0.75% byweight carbidopa, and about 14% to about 16% by weight arginine. Anotherexemplary pharmaceutical composition may include about 6% by weightlevodopa, about 0.75% by weight carbidopa, about 14% to about 16% byweight arginine, about 0.5% ascorbic acid and about 0.5% NAC.

According to some embodiments, the first pharmaceutical composition ofthe invention comprises between about 5.0 to about 10.0% w/v, betweenabout 10.0 to about 15.0% w/v, between about 15.0 to about 20.0% w/v,between about 20.0 to about 25.0% w/v, between about 25.0 to about 30.0%w/v, between about 30.0 to about 35.0% w/v, between about 35.0 to about40.0% w/v, between about 40.0 to about 45.0% w/v, between about 45.0 toabout 50.0% w/v, between about 50.0 to about 55.0% w/v, between about55.0 to about 60.0% w/v, between about 60.0 to about 65.0% w/v, betweenabout 65.0 to about 70.0% w/v, between about 70.0 to about 75.0% w/v,between about 75.0 to about 80.0% w/v of a solvent, e.g., NMP, a bufferor any other co-solvent.

According to some embodiments, the first pharmaceutical compositionfurther comprises a buffer. According to some embodiments, the buffer isselected from citrate buffer, citric acid buffer, sodium acetate buffer,acetic acid buffer, tartaric acid buffer, phosphate buffer, succinicacid buffer, Tris buffer, glycine buffer, hydrochloric acid buffer,potassium hydrogen phthalate buffer, sodium buffer, sodium citratetartrate buffer, sodium hydroxide buffer, sodium dihydrogen phosphatebuffer, disodium hydrogen phosphate buffer, tromethamine (TRIS), or anycombination thereof. The first pharmaceutical composition may comprisebetween about 0.1 to about 30.0% w/v of a buffer. According to someembodiments, the first pharmaceutical composition comprises betweenabout 0.1 to about 1.0% w/v, between about 1.0 to about 2.0% w/v,between about 2.0 to about 3.0% w/v, between about 3.0 to about 4.0%w/v, between about 4.0 to about 5.0% w/v, between about 5.0 to about6.0% w/v, between about 6.0 to about 7.0% w/v, between about 8.0 toabout 9.0% w/v, between about 9.0 to about 10.0% w/v, between about 10.0to about 15.0% w/v, between about 15.0 to about 20.0% w/v, between about20.0 to about 25.0% w/v, between about 25.0 to about 30.0% w/v of abuffer.

According to some embodiments, the first pharmaceutical compositionsfurther comprises an acid or a base, e.g., in order to provide acomposition with a pre-defined pH. According to some embodiments, theacid is selected from HCl, HBr, methanesulfonic acid, ascorbic acid,acetic acid, citric acid, or any combination thereof. According to someembodiments, the base is selected from NaOH, Ca(OH)₂, ammoniumhydroxide, arginine, magnesium hydroxide, potassium hydroxide,meglumine, tromethamine (TRIS), triethylamine, diisopropylethylamine,diazabicycloundecene or any combination thereof. The firstpharmaceutical compositions may comprise between about 0.1 to about30.0% w/v of a base or acid. According to some embodiments, the firstpharmaceutical composition comprises between about 0.1 to about 1.0%w/v, between about 1.0 to about 2.0% w/v, between about 2.0 to about3.0% w/v, between about 3.0 to about 4.0% w/v, between about 4.0 toabout 5.0% w/v, between about 5.0 to about 6.0% w/v, between about 6.0to about 7.0% w/v, between about 8.0 to about 9.0% w/v, between about9.0 to about 10.0, between about 10.0 to about 11.0, between about 11.0to about 12.0, between about 12.0 to about 13.0, between about 13.0 toabout 14.0, between about 14.0 to about 15.0, between about 15.0 toabout 16.0, between about 16.0 to about 17.0, between about 17.0 toabout 18.0, between about 18.0 to about 19.0, between about 19.0 toabout 20.0, between about 20.0 to about 21.0, between about 21.0 toabout 22.0, between about 22.0 to about 23.0, between about 23.0 toabout 24.0, between about 24.0 to about 25.0, between about 25.0 toabout 26.0, between about 26.0 to about 27.0, between about 27.0 toabout 28.0, between about 28.0 to about 29.0, between about 29.0 toabout 30.0, of a base or acid.

The pH of the first pharmaceutical composition of the invention may bebetween about 4.5 to about 10 at about 25° C. According to someembodiments, the pH of the first pharmaceutical compositions is betweenabout 4.5 to about 5 at about 25° C. According to some embodiments, thepH of the first pharmaceutical compositions is between about 5 to about6 at about 25° C. According to some embodiments, the pH of the firstpharmaceutical compositions is between about 6 to about 7 at about 25°C.

According to some embodiments, the pH of the first pharmaceuticalcompositions is between about 7 to about 8 at about 25° C. According tosome embodiments, the pH of the first pharmaceutical compositions isbetween about 8 to about 9 at about 25° C. According to someembodiments, the pH of the first pharmaceutical compositions is betweenabout 9 to about 10 at about 25° C. According to some embodiments, thepH of the first pharmaceutical compositions is between about 4.5 toabout 5.5 at about 25° C. According to some embodiments, the pH of thefirst pharmaceutical compositions is between about 5.5 to about 6.5 atabout 25° C. According to some embodiments, the pH of the firstpharmaceutical compositions is between about 6.5 to about 7.5 at about25° C. According to some embodiments, the pH of the first pharmaceuticalcompositions is between about 7.5 to about 8.5 at about 25° C. Accordingto some embodiments, the pH of the first pharmaceutical compositions isbetween about 8.5 to about 9.5 at about 25° C. According to someembodiments, the pH of the first pharmaceutical compositions is betweenabout 9.5 to about 10 at about 25° C. According to some embodiments, thepH of the first pharmaceutical compositions is about 9.5 at about 25° C.According to some embodiments, an acid or a base is added to the firstpharmaceutical composition in order to provide a composition with apredefined pH value. According to some embodiments, the acid is selectedfrom HCl, HBr, methanesulfonic acid, ascorbic acid, acetic acid, citricacid, or any combination thereof. According to some embodiments, thebase is selected from NaOH, arginine, an amine base, any of the basesmentioned herein, and any combination thereof.

According to some embodiments, the second pharmaceutical composition isadministered when desired and/or required, e.g., when symptoms from saidneurological or movement disorder require such administration, oraccording to a predefined treatment protocol. The assessment of thetiming for administering the second pharmaceutical composition may beperformed by a caretaker, a physician, the patient to whom thecomposition is being administered, or any combination thereof, resultingfrom consultation and/or joint decision making, and the like. Accordingto some embodiments, a system supported by any type of sensors mayprovide data for determining the need for administering the secondpharmaceutical composition. That data may be delivered to a caretaker, aphysician, the patient, or any combination thereof, via any means, suchas an electronic device, e.g., a smartphone, dedicated console, tablet,email, dedicated or known application, and the like.

According to some embodiments, the second pharmaceutical composition isadministered at predefined times, predefined intervals, or both, set,e.g., according to treatment protocols or according to data receivedfrom the patient, caregiver, physician, sensors, and the like. Thepredetermined times and/or intervals may be reset at any time point,e.g., in view of data received from the patient, caretaker, sensors,physician assessment, and the like.

According to some embodiments, the second pharmaceutical composition isorally administered substantially concurrently with the start of theinfusion time course. According to some embodiments, the secondpharmaceutical composition is orally administered about 1, 2, 3, 4, or 5hours after the start of the infusion time course. It is noted that the“start of the infusion time course” may be a daily time, wherein thecycle of the infusion, e.g., when new vials are introduced into thesystem, when a cartridge is replaced, when an infusion set is replaced,and the like.

According to some embodiments, the orally administered secondpharmaceutical composition is a morning oral dose. According to someembodiments, the morning oral dose comprises levodopa, a levodopa salt,a levodopa prodrug, or any combination thereof. According to someembodiments, the morning oral dose includes one of: 25 mg levodopa, 50mg levodopa, 75 mg levodopa, 95 mg levodopa, 100 mg levodopa, 125 mglevodopa, 145 mg levodopa, 150 mg levodopa, 195 mg levodopa, 200 mglevodopa, 245 mg levodopa, or 250 mg levodopa.

According to some embodiments, the morning oral dose comprises (a)levodopa, a levodopa salt, a levodopa prodrug; (b) a dopa decarboxylaseinhibitor (DDCI), a DDCI salt, a DDCI prodrug, or (c) any combinationthereof

According to some embodiments the second pharmaceutical composition isadministered up to 20 times a day. According to some embodiments, thesecond pharmaceutical composition is administered about 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11 or 12 times a day. According to some embodiments, thesecond pharmaceutical composition is administered between about 3 and 7times a day. According to some embodiments, the second pharmaceuticalcomposition is administered between about 4 and 6 times a day. Accordingto some embodiments, the second pharmaceutical composition isadministered at a frequency of between about 30 minutes to about 24hours. According to some embodiments, the second pharmaceuticalcomposition is administered at a frequency of between about 30 minutesto about one hour, between about one hour to two hours, between abouttwo hours to three hours, between about three hours to about four hours,between about four hours to about five hours, between about five hoursto about six hours, between about six hours to seven five hours, betweenabout seven hours to about eight hours, between about eight hours toabout nine hours, between about nine hours to about 10 hours, betweenabout 10 hours to about 11 hours, between about 11 hours to about 12hours, between about 12 hours to about 13 hours, between about 13 hoursto about 14 hours, between about 14 hours to about 15 hours, betweenabout 15 hours to about 16 hours, between about 16 hours to about 17hours, between about 17 hours to about 18 hours, between about 18 hoursto about 19 hours, between about 19 hours to about 20 hours, betweenabout 20 hours to about 21 hours, between about 21 hours to about 22hours, between about 22 hours to about 23 hours, between about 23 hoursto about 24 hours.

The intervals between one administration to the next may differ as well,depending, e.g., on the patient's/caretaker's/physician's observationsand assessment, on data received from any type of appropriate sensor, ona predefined treatment protocol, any combination thereof, and the like.

According to some embodiments, the administered dose of the levodopamoiety in the second pharmaceutical composition is the same each time itis administered. According to some embodiments, the dose of the levodopamoiety in the second pharmaceutical composition may differ betweendifferent administrations. According to some embodiments, the dose ofthe levodopa moiety in the second pharmaceutical composition is betweenabout 10 mg per day and about 3000 mg per day, between about 10 mg perday and about 50 mg per day, between about 50 mg per day and about 100mg per day, between about 100 mg per day and about 150 mg per day,between about 150 mg per day and about 250 mg per day, between about 250mg per day and about 350 mg per day, between about 350 mg per day andabout 500 mg per day, between about 500 mg per day and about 750 mg perday, between about 750 mg per day and about 1000 mg per day, betweenabout 1000 mg per day and about 1250 mg per day, between about 1250 mgper day and about 1500 mg per day, between about 1500 mg per day andabout 1750 mg per day, between about 1750 mg per day and about 2000 mgper day, between about 2000 mg per day and about 2250 mg per day,between about 2250 mg per day and about 2500 mg per day, between about2500 mg per day and about 2750 mg per day, or between about 2750 mg perday and about 3000 mg per day. According to some embodiments, the doseof the levodopa moiety in the second pharmaceutical composition isbetween about 100 mg per day to about 1800 mg per day. According to someembodiments, the dose of the levodopa moiety in the secondpharmaceutical composition is between about 350 mg per day to about 700mg per day.

It is noted that an administered dose is defined according to the timein which the composition is administered to the patient, and therefore,if several tablets, e.g., 4 tablets, each comprising 100 mg of levodopaare administered to the patient at practically the same time, theadministered dose of the levodopa in the second pharmaceuticalcomposition would be considered to be 400 mg in such an instance.Further, the dose per day may consist of several administered doses, notnecessarily identical to one another, e.g., a patient may beadministered 100 mg at 8 am, 200 mg at 10 am, 100 mg at 3 pm and 75 mgat 7 pm, such that the dose of the levodopa moiety in the secondpharmaceutical composition would be considered to be 475 mg per day.

According to some embodiments, the dose of the levodopa moiety in thesecond pharmaceutical composition is between about 10 mg and about 500mg per administration, between about 10 mg and about 25 mg peradministration, between about 25 mg and about 50 mg per administration,between about 50 mg and about 75 mg per administration, between about 75mg and about 100 mg per administration, between about 100 mg and about150 mg per administration, between about 150 mg and about 200 mg peradministration, between about 200 mg and about 250 mg peradministration, between about 250 mg and about 300 mg peradministration, between about 300 mg and about 350 mg peradministration, between about 350 mg and about 400 mg peradministration, between about 400 mg and about 450 mg peradministration, between about 450 mg and about 500 mg peradministration. According to some embodiments, the dose differs betweendifferent administrations. According to other embodiments, the doseremains constant for at least two administrations, e.g., over the courseof 24 hours, three days, one week, and the like.

In certain embodiments, the dose of the levodopa moiety in the secondpharmaceutical composition is about 50 mg, 75 mg, 100 mg, 125 mg, 150mg, 200 mg, or 250 mg levodopa, e.g., in an immediate release tablet orcapsule. According to some embodiments, the dose of the levodopa moietyin the second pharmaceutical composition is about 95 mg, about 145 mg,about 195 mg, or about 245 mg levodopa, e.g., in an extended releaseform, e.g., a tablet or capsule.

As mentioned above, the levodopa moiety may be levodopa, a levodopasalt, a levodopa prodrug or any combination thereof. According to someembodiments, the levodopa moiety is levodopa.

According to some embodiments, the dose of the carbidopa moiety in thesecond pharmaceutical composition is between about 2.5 mg and about 50mg per administration, between about 2.5 mg and about 20 mg peradministration, between about 2.5 mg and about 25 mg per administration,between about 2.5 mg and about 35 mg per administration, between about2.5 mg and about 40 mg per administration, between about 15 mg and about20 mg per administration, between about 15 mg and about 25 mg peradministration, between about 15 mg and about 35 mg per administration,between about 15 mg and about 40 mg per administration, between about 15mg and about 50 mg per administration, between about 20 mg and about 25mg per administration, between about 20 mg and about 35 mg peradministration, between about 20 mg and about 40 mg per administration,between about 20 mg and about 50 mg per administration, between about 25mg and about 35 mg per administration, between about 25 mg and about 40mg per administration, between about 25 mg and about 50 mg peradministration, between about 35 mg and about 40 mg per administration,between about 35 mg and about 50 mg per administration, between about 40mg and about 50 mg per administration. According to some embodiments,the dose of carbidopa moiety in the second pharmaceutical compositioncomprises 2.5 mg, 18.57 mg, 25 mg, 31.25 mg, 37.5 mg or 50 mg carbidopa.

The second pharmaceutical composition may be in any appropriate oralform, such as a pill, hard or soft capsule, tablet, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,syrups or elixirs. The second pharmaceutical composition may animmediate release form, or any type of controlled release form, such assustained release, extended release, delayed release, prolonged release,and the like. As noted above, the second pharmaceutical composition maycomprise at least two active ingredients, e.g., levodopa and carbidopa.It is noted that each one of the active ingredients in the secondpharmaceutical composition may be formulated in a different releaseform, for instance, the levodopa may be in a controlled release form,while the carbidopa is in an immediate release form, or vice versa.

According to some embodiments, the second pharmaceutical formulation isadministered only during high activity/waking hours, e.g., during theday, such that the administration intervals are smaller during highactivity/waking hours than during other parts of the day, e.g., lowactivity/night hours. According to further embodiments, the doses of thesecond pharmaceutical formulation provided during high activity/wakinghours are higher than the doses administered during other parts of theday, e.g., low activity/night hours. According to some embodiments, adosing regimen over 24 hours is devised and may remain constant for acertain number of days, while, within the same day the regimen may bedifferent based on wakefulness, activity, and the like. According tosome embodiments, the dosing regimen may change from day to day, as wellas within the same day.

Embodiments of the invention are further directed to a method fortreatment of a neurological or movement disorder, such as Parkinson'sdisease, in a patient in need thereof, wherein the method comprises:

parenterally administering a first pharmaceutical compositioncomprising:

-   -   levodopa, a levodopa salt, a levodopa prodrug, or any        combination thereof; and a dopa decarboxylase inhibitor (DDCI),        a DDCI salt, a DDCI prodrug, or any combination thereof;

-   and, concomitantly,

orally administering a morning oral dose composition comprising:

-   -   levodopa, a levodopa salt, a levodopa prodrug; a dopa        decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI prodrug; or        any combination thereof.

Further embodiments of the invention are directed to

a first pharmaceutical composition comprising:

-   -   levodopa, a levodopa salt, a levodopa prodrug, or any        combination thereof; and    -   a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI        prodrug, or any combination thereof;

-   and,

a second pharmaceutical composition comprising:

-   -   levodopa, a levodopa salt, a levodopa prodrug;    -   a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI        prodrug; or any combination thereof,

for use as a combination in the treatment of a neurological or movementdisorder, for example, Parkinson's disease, wherein the firstpharmaceutical composition is formulated as a parenteral composition andthe second pharmaceutical composition is formulated as an oralcomposition.

Further embodiments of the invention are directed to a kit comprising:

a first pharmaceutical composition in parenteral form comprising:

-   -   levodopa, a levodopa salt, a levodopa prodrug, or any        combination thereof; and a dopa decarboxylase inhibitor (DDCI),        a DDCI salt, a DDCI prodrug, or any combination thereof;

a second pharmaceutical composition in oral form comprising:

-   -   levodopa, a levodopa salt, a levodopa prodrug;    -   a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCI        prodrug; or any combination thereof; and

-   instructions for the concomitant administration of the first    pharmaceutical composition and the second pharmaceutical composition    for the treatment of a neurological or movement disorder, such as    Parkinson's disease.

Further embodiments of the invention are directed to a kit comprising:

a first pharmaceutical composition in parenteral form comprising:

levodopa, a levodopa salt, a levodopa prodrug, or any combinationthereof; and a dopa decarboxylase inhibitor (DDCI), a DDCI salt, a DDCIprodrug, or any combination thereof; and

instructions for the concomitant administration of the firstpharmaceutical composition and a second pharmaceutical composition forthe treatment of a neurological or movement disorder, such asParkinson's disease, wherein the second pharmaceutical composition isprovided separately.

Further embodiments of the invention are directed to a method oftreating Parkinson's disease in a patient in need thereof, wherein thepatient was previously administered a previous form of levodopa otherthan immediate release carbidopa-levodopa tablets in a ratio of 1:4, andwherein the method comprises:

-   -   converting the patient from the previous form of levodopa to        oral immediate release levodopa-carbidopa 100/25 mg tablets;    -   subcutaneously administering to the patient, over a subcutaneous        infusion time course of at least about 24 hours or more, a first        pharmaceutically acceptable liquid composition comprising        levodopa; and    -   orally administering to the patient, before or during the        subcutaneous infusion time course, at least one oral dosage form        comprising levodopa.

Further embodiments of the invention are directed to a method oftreating Parkinson's disease in a patient in need thereof, wherein thepatient was previously administered a previous form of levodopa, andwherein the method comprises:

-   -   converting the patient from the previous form of levodopa to an        oral immediate release levodopa-carbidopa form;    -   after said conversion, subcutaneously administering to the        patient, over a subcutaneous infusion time course of at least        about 24 hours or more, a first pharmaceutically acceptable        liquid composition comprising levodopa; and    -   orally administering to the patient, before or during the        subcutaneous infusion time course, at least one oral dosage form        comprising levodopa.

Further embodiments of the invention are directed to a method oftreating Parkinson's disease in a patient in need thereof, wherein thepatient was previously administered a previous form of levodopa, andwherein the method comprises:

-   -   converting the patient from the previous form of levodopa to an        oral immediate release levodopa form, thus administering an        amount of oral immediate release levodopa to said patient;    -   following said conversion, subcutaneously administering to the        patient, over a subcutaneous infusion time course of at least        about 24 hours or more, a first pharmaceutically acceptable        liquid composition comprising a subcutaneous amount of levodopa,        wherein        -   if the amount of oral immediate release form of levodopa is            higher than the subcutaneous amount of levodopa, the amount            of oral immediate release form of levodopa is reduced by            about the amount of the subcutaneous amount of levodopa and            the patient is administered a remaining amount of oral            immediate release levodopa; and        -   if the amount of oral immediate release form of levodopa is            lower than the subcutaneous amount of levodopa, the patient            is not administered the oral immediate release form of            levodopa except for a morning dose of oral immediate release            levodopa, administered before or during the subcutaneous            infusion time course.

Further embodiments of the invention are directed to a method oftreating Parkinson's disease in a patient in need thereof, wherein thepatient was previously administered with a previous form of levodopa,and wherein the method comprises:

-   -   converting the patient from the previous form of levodopa to an        oral immediate release levodopa form, thus administering an        initial daily amount of oral immediate release levodopa to said        patient;    -   following said conversion, subcutaneously administering to the        patient, over a subcutaneous infusion time course of at least        about 24 hours or more, a first pharmaceutically acceptable        liquid composition in an amount to deliver about 720 mg of        levodopa to the patient over the course of at least about 24        hours, wherein        -   if the initial daily amount of oral immediate release form            of levodopa is higher than about 700 mg, the amount oral            immediate release form of levodopa is reduced by about 700            mg and the patients is administered with a remaining amount            of oral immediate release levodopa, equal to the initial            daily amount of oral immediate release levodopa minus 700            mg; and        -   if the initial daily amount of amount of oral immediate            release form of levodopa is lower than about 700 mg, the            patient is administered only with a morning dose of oral            immediate release levodopa, administered before or during            the subcutaneous infusion time course.

In certain embodiments of the methods described herein, the concomitantadministration of the first composition (parenteral, e.g., subcutaneousadministration) and the second composition (e.g., oral tablet) to thepatient results in a higher area under the curve (AUC) for levodopa fromtime 0 to the end of the parenteral, e.g., subcutaneous, infusion ascompared to the combined AUC for levodopa in the patient when the firstcomposition and the second composition are not concomitantlyadministered, wherein the total amount of levodopa administered is thesame, whether administered concomitantly or non-concomitantly.

Unless explicitly stated, the method embodiments described herein arenot constrained to a particular order or sequence. Additionally, some ofthe described method embodiments or elements thereof can occur or beperformed simultaneously, at the same point in time, or concurrently.

It is appreciated that certain features of the invention may also beprovided in combination in a single embodiment. Conversely, variouselements of the invention that are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable sub-combination or as suitable in any other describedembodiment of the invention. Further, certain features described in thecontext of various embodiments are not to be considered essentialfeatures of those embodiments, unless the embodiment is inoperativewithout those elements.

Various embodiments and aspects of the present invention as delineatedhereinabove and as claimed in the claims section below may be supportedby the following examples; however, they are not to be limited by theexamples.

EXAMPLES Example 1 Synergism

A test was run in order to assess the plasma exposure of levodopa (LD)following the coadministration of LD and carbidopa (CD) in bothsubcutaneous (SC) and oral administrations. Accordingly, resultsobtained from a combined SC+oral administration were compared to resultsobtained from SC administration alone and from oral administrationalone. An additive plasma exposure and PK profile was expected, i.e., itwas expected that the SC+oral coadministration would provide resultsequal to the additive results of the SC and oral administrations, wheneach was administered separately.

Methods

16 healthy subjects (18-50 years) were treated in a crossover manner,i.e., sequentially, with a washout period of 6 days between thefollowing two treatments:

Treatment A: A total dose of 180/22.5 mg LD/CD (formulation A) wasadministered by SC infusion over the course of 8 hours, at a steadyinfusion rate.

Treatment B: An immediate release (IR) tablet of 100/25 mg LD/CD wasadministered orally at time 0 h.

Following a 32 hour washout period, the same 16 healthy subjects wereadministered with LC/CD both orally and subcutaneously according to thefollowing treatment:

Treatment C: A dose of 153.6/19.2 LD/CD (formulation A) was administeredby SC infusion over the course of 8 hours, at a steady infusion rate,combined with a single co-administration of an oral IR LD/CD 100/25 mgtablet, 4 hours after the initiation of the infusion. Total LD/CD dose:253.6/44.2 mg.

Blood samples were collected at the following time points:

Treatment A: 0 (prior to treatment initiation), 0.5 h, 1 h, 2 h, 3 h, 4h, 5 h, 5.5 h, 6 h, 7 h, 8 h (prior to the end of the infusion).

Treatment B: 0 (prior to treatment initiation), 0.5 h, 1 h, 2 h, 3 h, 4h.

Treatment C: 0 (prior to treatment initiation), 0.5 h, 1 h, 2 h, 3 h, 4h, 4.5 h, 5 h, 5.5 h, 6 h, 7 h, 8 h (prior to the end of the infusion).

Results

The normalized AUC₀₋₈ of LD and CD of Treatment C, resulting from thecombined SC and oral treatment, as described above, was calculated andcompared to the sum of the normalized LD and CD AUCs obtained fromTreatment A (AUC₀₋₈ resulting from 8 h SC infusion) and Treatment B(AUC₀₋₄ resulting from one IR oral tablet). The results are presented inthe Tables 1 and 2 below.

TABLE 1 Observed .vs. Calculated Ratios of LD AUCs Resulting from SC,Oral, and SC + Oral Treatments Observed 3. Combined 4. Treatment C(C) 1. Treatment A AUC 2. Treatment B 1 + 2 AUC (0-8) Additive ID (0-8)x0.853* AUC (0-4) [Estimated] [Observed] Ratio 1001 2266 + 1327 = 35934092 vs. 1.139 1002 2218 + 1434 = 3652 3961 vs. 1.085 1003 2620 + 1752 =4372 5136 vs. 1.175 1004 1729 + 919 = 2648 3508 vs. 1.325 1005 2031 +969 = 3000 4105 vs. 1.368 1006 2693 + 1885 = 4578 6325 vs. 1.382 10082603 + 986 = 3589 5031 vs. 1.402 1009 1920 + 1167 = 3087 3889 vs. 1.2601010 2575 + 1375 = 3950 4175 vs. 1.057 1011 3686 + 2658 = 6344 7678 vs.1.210 1012 2310 + 1419 = 3729 4772 vs. 1.280 1013 3087 + 1799 = 48865620 vs. 1.150 1014 2196 + 1426 = 3622 5059 vs. 1.397 1015 2629 + 1812 =4441 5861 vs. 1.320 1016 2236 + 1837 = 4073 4610 vs. 1.132 GeomeanIndividual 1.240 Geomean 2412 + 1458 = 3870 4817 vs. 1.245 Group*Treatment A AUC multiplied by 0.853 in order to provide a dose equal tothe subcutaneous dose of Treatment C. It is noted in this respect thatprevious studies (not shown) proved the dose proportionality ofsubcutaneous levodopa and carbidopa, and therefore, comparison betweendoses is by linear normalization.

TABLE 2 Observed .vs. Calculated Ratios of CD AUCs Resulting from SC,Oral, and SC + Oral Treatments 4. Observed 3. Combined Treatment (C) 1.Treatment A AUC 2. Treatment B 1 + 2 C AUC (0-8) Additive ID (0-8)x0.853* AUC (0-4) [Estimated] [Observed] Ratio 1001 850 + 256 = 1106 917vs. 0.829 1002 827 + 290 = 1117 973 vs. 0.871 1003 925 + 266 = 1191 1086vs. 0.912 1004 773 + 219 = 992 1000 vs. 1.008 1005 942 + 246 = 1188 1181vs. 0.994 1006 955 + 322 = 1277 1218 vs. 0.954 1008 988 + 349 = 13371047 vs. 0.783 1009 657 + 318 = 975 754 vs. 0.773 1010 880 + 322 = 1202995 vs. 0.828 1011 1231 + 513 = 1744 1358 vs. 0.779 1012 855 + 300 =1155 868 vs. 0.752 1013 1017 + 459 = 1476 1200 vs. 0.813 1014 770 + 297= 1067 1152 vs. 1.080 1015 1120 + 252 = 1372 1255 vs. 0.915 1016 859 +351 = 1210 936 vs. 0.774 Geomean Individual 0.866 Geomean 900 + 309 =1209 1051 vs. 0.869 Group *Treatment A AUC multiplied by 0.853 in orderto provide a dose equal to the subcutaneous dose of Treatment C. It isnoted in this respect that previous studies (not shown) proved the doseproportionality of subcutaneous levodopa and carbidopa, and therefore,comparison between doses is by linear normalization.

It was expected that the combined/additive results of Treatments A and B(combined, i.e., added to one another), would be practically the same asthe results obtained from Treatment C, which essentially combinesTreatments A and B within its treatment regime.

Surprisingly, as presented in the results above, the comparison of theTreatment C normalized AUC₀₋₈, with the sum of the normalized AUCs forTreatments A and B, as described above, demonstrated a higher thanexpected LD AUC, while, in contrast, the CD AUC for Treatment C waslower than expected.

Specifically, as presented in Table 1, the ratio of the LD normalizedAUCs resulting from Treatment C, compared to those obtained inTreatments A+B (addition of both to simulate the SC + oraladministration in Treatment C) for each individual was above 1.0, with amean ratio of 1.245, and a range of from 1.057 to 1.402. Further, aspresented in Table 2, the ratio of the CD normalized AUCs resulting fromTreatment C, compared to those obtained in Treatments A+B, for mostindividuals was below 1.0, with a mean ratio of 0.869 and a range offrom 0.773 to 1.080.

Thus, surprisingly, the combined SC+oral treatment provides LD levelshigher than expected from the addition of the two types ofadministrations, when each is provided separately. In contrast, the CDlevels obtained from the combined SC+oral treatment are lower thanexpected from the addition of the two types of administrations, wheneach is provided separately. The low CD results obtained in the combinedtreatment render the higher than expected LD levels even moresurprising—even though the amount of CD is reduced, the amount of LDactually rises, which is opposite than what would have been expected,since generally, the CD inhibits the peripheral metabolism of LD andtherefore, the lower the amount of CD, the lower the expected amount ofLD would be.

Example 2 Dose Proportionality Example 2a

Dose proportionality of LD and CD administered subcutaneously wasdemonstrated in a clinical trial (ND0612-001, a single dose,single-center, randomized, double-blind, placebo controlled, doseescalation study in healthy male subjects).

Subjects were administered with a composition comprising LD (6% w/w)/CD(1.4% w/w) by way of a 24 hour continuous infusion at varying infusionrates:

-   Group 1: 80 μl/h-   Group 2: 120 μl/h-   Group 3: 160 μl/h-   Group 4: 200 μl/h-   Group 5: 240 μl/h    Several PK parameters were derived for both LD and CD in the dose    proportionality assessment, including AUC (hr*ng/mL), Cmax (ng/mL),    C15 (ng/mL), and C24 (ng/mL).

All analyses performed for all PK parameters studied demonstrated doseproportionality for both LD and CD. Reference is made to FIG. 1, whichpresents the mean plasma levodopa concentration of the five testedgroups .vs. the time (in hours) after subcutaneous infusion initiation.As clearly shown in FIG. 1, the levodopa plasma levels are dependent onthe administered dose of levodopa and are proportional to one another.Similar results were obtained for carbidopa.

Example 2b

In a separate clinical trial (ND0612-005a and ND0612-005b, open labeldesign studies), the plasma carbidopa levels were tested in view of thesubcutaneous administration of several carbidopa doses. Threeformulations, comprising 60 mg/ml levodopa and (a) 7.5 mg/ml; (b) 6mg/ml; or 4 mg/ml of carbidopa, were administered to three groups ofsubjects over the course of 24 hours, providing a total of 17.9 mg/24 hcarbidopa to each subject in the first group, 26.9 mg/24 h carbidopa toeach subject in the second group and 33.6 mg/24 h carbidopa to eachsubject in the third group. The obtained carbidopa Cmax values showedclear dose proportionality (see FIG. 2).

Equivalents

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. Manyvariations of the invention will become apparent to those skilled in theart upon review of this specification. The full scope of the inventionshould be determined by reference to the claims, along with their fullscope of equivalents, and the specification, along with such variations.

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about”. It should be noted that where particular values aredescribed in the description and claims, unless otherwise stated, theterm “about” means that an acceptable error range, e.g., up to 5% or10%, for the particular value should be assumed.

INCORPORATION BY REFERENCE

The entire contents of all patents, published patent applications,websites, and other references cited herein are hereby expresslyincorporated herein in their entireties by reference.

1. A method for treatment of Parkinson's disease in a patient in needthereof, said method comprising: subcutaneously administering to thepatient, over a subcutaneous infusion time course of about 24 hours ormore, a first pharmaceutically acceptable liquid composition comprising:levodopa, carbidopa, arginine, and an antioxidant, in an amount todeliver about 720 mg of levodopa and about 90 mg of carbidopa to thepatient over the course of about 24 hours; and orally administering tothe patient, before or during the subcutaneous infusion time course, atleast one oral dosage form comprising levodopa.
 2. The method of claim1, wherein the oral dosage form includes one of: about 50 mg levodopa,about 75 mg levodopa, about 95 mg levodopa, about 100 mg levodopa, about125 mg levodopa, about 145 mg levodopa, about 150 mg levodopa, about 195mg levodopa, about 200 mg levodopa, about 245 mg levodopa, or about 250mg levodopa.
 3. The method according to claim 1, wherein the treatmentincludes the treatment of motor fluctuations.
 4. The method according toclaim 1, wherein the oral dosage form is a morning oral dose.
 5. Amethod for treatment of Parkinson's disease in a patient in needthereof, wherein the method comprises: subcutaneously administering tothe patient, over a subcutaneous infusion time course of about 24 hoursor more, a first pharmaceutical composition comprising: a levodopamoiety and a carbidopa moiety, and, concomitantly, orally administeringto the patient, before or during the subcutaneous infusion time course,at least one oral dosage form comprising levodopa.
 6. The methodaccording to claim 5, wherein the first pharmaceutical compositioncomprises the levodopa moiety and the carbidopa moiety in a ratio ofabout 8:1 w/w.
 7. The method according to claim 5, wherein the treatmentincludes the treatment of motor fluctuations.
 8. The method according toclaim 5, wherein the first pharmaceutical composition comprises up toabout 720 mg levodopa and up to about 90 mg carbidopa, administered overthe course of about 24 hours, wherein the levodopa and carbidopa are ina ratio of about 8:1 w/w.
 9. The method according to claim 5, whereinthe first pharmaceutical composition comprises about 370 mg to about 720mg levodopa and about 46 mg to about 90 mg carbidopa administered overthe course of about 24 hours, wherein the levodopa and carbidopa are ina ratio of about 8:1 w/w.
 10. The method according to claim 5, whereinthe oral dosage form is a morning oral dose.
 11. A method for treatmentof Parkinson's disease in a patient in need thereof, said methodcomprising: subcutaneously administering to the patient, over asubcutaneous infusion time course of about 24 hours or more, a firstpharmaceutically acceptable liquid composition comprising: levodopa andcarbidopa, in an amount to deliver levodopa and carbidopa in a ratio ofabout 8:1 w/w to the patient over the course of about 24 hours; andorally administering to the patient, before or during the subcutaneousinfusion time course, at least one oral dosage form comprising levodopa.12. The method according to claim 11, wherein the treatment includes thetreatment of motor fluctuations.
 13. The method according to claim 11,wherein the pharmaceutically acceptable liquid composition comprisinglevodopa and carbidopa, in an amount to deliver about 370 to about 720mg of levodopa and about 46 to about 90 mg of carbidopa to the patientover the course of about 24 hours.
 14. A method for treatment ofParkinson's disease in a patient in need thereof, said methodcomprising: subcutaneously administering to the patient, over asubcutaneous infusion time course of about 24 hours or more, a firstpharmaceutically acceptable liquid composition comprising: levodopa andcarbidopa, in an amount to deliver about 370 to about 720 mg of levodopaand about 46 to about 90 mg of carbidopa to the patient over the courseof about 24 hours; and orally administering to the patient, before orduring the subcutaneous infusion time course, at least one oral dosageform comprising levodopa.
 15. The method according to claim 14, whereinthe first pharmaceutically acceptable liquid composition compriseslevodopa and carbidopa in a ratio of about 8:1 w/w.
 16. The methodaccording to claim 14, wherein the treatment includes the treatment ofmotor fluctuations.